ANTISENSE MODULATION OF PECAM-1

Abstract: Compositions and methods for the treatment and diagnosis of diseases or disorders amenable to treatment through modulation of expression of a nucleic acid encoding a platelet endothelial cell adhesion molecule-1 (PECAM-1; also known as CD31 antigen or endoCAM) protein are provided.

Description: ANTISENSE MODULATION OF PECAM-1 FIELD OF THE INVENTION The present invention provides compositions and methods for detecting and modulating levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) proteins, including human PECAM-1 (also known as CD31 antigen or endoCAM) . In particular, the invention relates to antisense compounds specifically hybridizable with nucleic acids encoding PECAM-1 proteins. It has been found that such antisense compounds can modulate the expression of PECAM-1 proteins. PECAM-1 proteins are glycoproteins which are expressed on the surfaces of a variety of cell types (for reviews of PECAM-1 proteins, see Newman, J. Clin . Inves t . , 1997, 99, 3 and DeLisser et al . , Immunol . Today, 1994, 15, 490). Because PECAM-1 mediates cell-cell interactions, modulation of the expression of PECAM- 1 allows for the control of such cell-cell interactions and resulting effects such as, for example, inflammation. The invention is thus directed to diagnostic methods for detecting, and prophylactic and therapeutic methods for preventing or inhibiting, respectively, PECAM-1-mediated processes. Furthermore, this invention is directed to treatment of conditions associated with abnormal expression of PECAM-1 proteins. This invention also relates to therapies, diagnostics, and research reagents for disease states or disorders which respond to modulation of the - 2 - expression of PECAM-1 proteins. Inhibition of the hyperproliferation of cells, and corresponding prophylactic, palliative and therapeutic effects result from treatment with the antisense compounds of the invention. BACKGROUND OF THE INVENTION Cell-cell interactions are a feature of a variety of biological processes. In the activation of the immune response, for example, one of the earliest detectable events in a normal inflammatory response is adhesion of leukocytes to the vascular endothelium, followed by migration of leukocytes out of the vasculature to the site of infection or injury. The adhesion of leukocytes to vascular endothelium is an obligate step in their migration out of the vasculature (Harlan, Blood, 1985, 65, 515) . As is well known in the art, cell-cell interactions are also critical for propagation of both B-lymphocytes and T-lymphocytes resulting in enhanced humoral and cellular immune responses, respectively. In several instances, the adhesion of one cell type to another is mediated by interactions between specific proteins, termed "adhesion molecules," located on the plasma membrane of cells. The interaction between adhesion molecules is similar to classical receptor ligand interactions with the exception that the ligand is fixed to the surface of a cell instead of being soluble. One group of related (by peptide sequence) , biologically significant molecules mediating cell- cell interactions are known in the art as CAMs (cellular adhesion molecules) . CAMs include, for example, several intercellular a . dhesion molecules (i.e., ICAM-1, ICAM-2 and ICAM-3) , eidothelial leukocyte adhesion molecule 1 (ELAM-1) , vascular . cell . adhesion molecule 1 (VCAM-1) . The nucleotide and peptide sequences of PECAM-1 (jolatelet endothelial . cellular a . dhesion molecule 1) indicate that it is also a member of the CAM family of genes. The CAM family is a part of the immunoglobulin superfamily of genes (Newman et al., Science, 1990, 247, 1219) . PECAM-1 is a member of the CAM family of proteins and is expressed on the surfaces of several cell types. Cells known to express PECAM-1 include, for example, endothelial cells, including human umbilical vein endothelial cells (HUVEC) , bovine aortic endothelial cells (BAEC) , glomerular endothelial (GEN) cells and cultured human pulmonary microvascular endothelial cells (HPMEC); platelets, monocytes, granulocytes, macrophages, some lymphocytes, some hematopoietic lineage cells and tumor cell lines from different mammalian species (see DeLisser et al., Immunol. Today, 1994, 15, 490. A variety of evidence indicates that PECAM-1 is involved in cell-cell recognition events (DeLisser et al., Immunol. Today, 1994, 15, 490) . For example, PECAM-1 mediates aggregation of L cells transfected with PECAM-1 cDNA (DeLisser et al., J. Biol. Chem., 1993, 268, 16307;) and, in certain T cell subsets, amplifies beta-1 integrin-mediated adhesion (Tanaka et al., J. Exp. Med., 1992, 116, 245) . In vitro studies have implicated PECAM-1 m the initiation of endothelial cell contact (Albelda et al., J. Cell Biol., 1990, 110, 1227) and capillary tube formation (Merwm et al., unpublished results cited in Vaporciyan et al., Science, 1993, 262, 1580) . In both m vitro and in vivo studies, PECAM-1 has been shown to be involved m the transmigration of white blood cells (e.g., neutrophils, monocytes, and other nucleated blood cells) through endothelial cell monolayers (Muller et al., J. Exp. Med., 1993, 178, 449). In addition to directly participating m cell-cell interactions, PECAM-1 apparently also regulates the activity and/or expression of other molecules involved in cellular interactions (Litwin et al . , J. Cel l Biol . , 1997, 139, 219) . In the development of the cardiovascular system, two different processes occur. Vasculogenesis is the initial differentiation of endothelial cells from mesoderm and the organization of these cells into defined blood vessels. Angiogenesis, on the other hand, is the budding and branching of vessels from preexisting vessels. PECAM-1 is expressed on presumptive endothelial cells during initial differentiation, and on all endothelial cells m the developing vasculature. De Lisser et al . , Trends Cardiovasc . Med . , 1997, 7, 203. Involvement of PECAM-1 in angiogenesis was demonstrated initially m endothelial cells cultured m the presence of antι-PECAM-1 antibodies. These cells failed to form the tight monolayers typical of cultured endothelial cells. This inhibition was reversible after removal of the antibody. Albelda et al . , J. Cell . Biol . , 1990, 110 , 1227. It has since been shown that monoclonal antibodies against human VE- cadhenn and PECAM-1 together inhibited vascular tube formation in m vi tro models of capillary tube formation and of wound healing m SCID mice. Matsumura et al . , J. Immunol . , 1997, 158 , 3408. Others have found that antibody inhibition of PECAM-1 alone blocked in vitro capillary tube formation and cytokine-induced corneal neovascularization . Monoclonal antibodies against PECAM-1 also blocked blood vessel growth m mouse models. Delisser et al . , Am . J. Pa thol . , 1997, 151 , 671. Thus it has been demonstrated both m vi tro and m vivo that PECAM-1 plays a critical role in angiogenesis. The role of PECAM-1 in vasculogenesis has also been demonstrated using a murine yolk sac model. PECAM-1 was also found to undergo dynamic phosphorylation, believed to be modulated by mtegrin association with extracellular matrix, during endothelial cell migration and vasculogenesis. Pinter et al . , Am . J. Pa thol . 1997, 150 , 1523. Due to PECAM-1 's involvement in cellular processes preceding inflammation and tumoπgenesis, it is believed that inhibitors of PECAM-1 expression may provide a novel therapeutic class of lmmunosuppressive and/or anti- mflammatory and antiproliferative agents with activity towards (1) autoimmune disorders such as multiple sclerosis, particularly autoimmune disorders of the thyroid such as Graves' disease, and undesired immune responses, such as, for example, those that occur in graft versus host disease (GVHD) ; (2) a variety of inflammatory diseases or disorders with an inflammatory component such as various forms of arthritis; allograft rejections; inflammatory diseases of the bowel, including Crohn' s disease; various dermatological conditions such as psoriasis; corneal inflammation and the like, (3) a variety of hyperproliferative diseases or disorders including, but not limited to, cancers, tumors, and the growth and spreading (metastasis) thereof, and (4), conditions associated with aberrant angiogenesis or vasculogenesis. To date, there are no known therapeutic agents which effectively prevent the expression of PECAM-1. Current agents which affect intercellular adhesion molecules include synthetic peptides, monoclonal antibodies, and soluble forms of the adhesion molecules. Synthetic peptides which block cellular interactions with PECAM-1 by mimicking a ligand of PECAM-1 have not been identified, although a peptidic mimic of PECAM-1 has been described (Liao et al . , J. Exp . Med. , 1997 , 185, 1349) . Monoclonal antibodies to PECAM-1 have been developed (Lastres et al . , J. Immunol . , 1994, 153, 4206) and may prove to be useful for the treatment of acute inflammatory responses or other conditions resulting from expression of PECAM-1 (Bogen et al . , J. Exp. Med. , 1994, 1 79, 1059; Murohara et al . , J. Immunol . , 1996, 156, 3550). However, with chronic treatment, the host animal can develop antibodies against the monoclonal antibodies themselves, thereby limiting their usefulness. In addition, monoclonal antibodies are large proteins which may have difficulty in gaining access to inflammatory sites. Soluble forms of the cell adhesion molecules suffer from many of the same limitations as monoclonal antibodies m addition to the expense of their production and their low binding affinity. All three of the above types of agents are polypeptides and are subject to proteolytic degradation in vivo, a feature which may limit the biological half-life and pharmacological effectiveness. Moreover, due to the high degree of homology between PECAM-1 and other members of the CAM family at the polypeptide level, agents which effect PECAM-1 activity might also effect other CAM proteins. Thus, there is a long felt need for molecules which effectively and specifically modulate PECAM-1 molecules. A number of angiogenesis inhibitors are currently being evaluated for combatting tumor growth and metastasis; however, none of these target PECAM-1. Antisense oligonucleotides avoid many of the pitfalls of current agents used to block the effects of PECAM-1. For example, antisense oligonucleotides are smaller than monoclonal antibodies and most synthetic peptides and are thus expected to have better access to sites of inflammation. A variety of chemical modifications are known which serve to enhance the affinity of an antisense oligonucleotide for its target nucleic acid. Other chemical modifications have been described that render synthetic oligonucleotides more resistant to n vi tro and m vivo degradation. Moreover, because of the degeneracy inherent in the genetic code, the homology between the nucleotide sequence of a nucleic acid which encodes a PECAM-1 protein and those nucleotide sequences encoding other CAM proteins will be less than the homology between the corresponding polypeptide sequences; as a result, antisense oligonucleotides have the potential to achieve a higher degree of specificity than many monoclonal antibodies. In short, the compounds of the invention are particularly effective for specifically modulating PECAM-1 molecules. RELATED ART U.S. Patent No. 5,264,554 to Newman describes PECAM-1 protein and variants thereof. See also PCT application WO 91/10683 published July 25, 1991. U.S. Patent No. 5,668,012 to Newman et al . describes PECAM-1 promoter sequences and sequences encoding PECAM-1 isoforms. See also PCT application WO 96/01271 published January 18, 1996. PCT application WO 97/10839, published March 27, 1997, describes synthetic peptides stated to inhibit binding of PECAM-1 monomers to each other. Liao et al . ( J. Exp . Med. , 1997, 185, 1349) describe fusion proteins comprising the soluble domain 1 of PECAM-1 and indicate that these fusion proteins are sufficient to modulate diapedesis in vivo and m vi tro . Berman et al . (J. Immunol . , 1996, 156, 1515) describe antibodies to PECAM-1 that are stated to modulate cellular transmigration events in vi tro . Murohara et al . (J. Immunol . , 1996, 156, 3550) describe a monoclonal antibody to human and feline PECAM-1 that is stated to inhibit leukocyte migration in glycogen-mduced peritonitis in vivo m cats. Lastres et al . (J. Immunol . , 1994, 153, 4206) describe antibodies and a phosphorothioate antisense oligonucleotide - 8 - targeted to the start (ATG) codon of PECAM-1 that inhibits cellular aggregation in an in vi tro assay. PECAM-1 mRNA or protein levels following treatment were not determined. Bogen et al . (J. Exp . Med. , 1994, 1 79, 1059) describe a monoclonal antibody to murine PECAM-1 and indicate that it modulates acute inflammation in thioglycollate-induced peritonitis in mice. Vaporciyan et al . { Science, 1993, 262, 1580) describe a monoclonal antibody to human PECAM-1 that cross-reacts with rat PECAM-1 and which is stated to modulate neutrophil transmigration in rats. Tang et al . ( J. Biol . Chem . , 1993, 268, 22883) describe antibodies to PECAM-1 stated to have the ability to decrease the in vi tro adhesion of tumor cells to microvascular endothelial cells. SUMMARY OF THE INVENTION In accordance with the present invention, antisense compounds are provided which specifically hybridize with a nucleic acid encoding a PECAM-1 protein. Certain antisense compounds of the invention are designed to bind either directly to mRNA transcribed from, or to a selected DNA portion of, a gene that encodes a PECAM-1 protein, thereby modulating the expression thereof. In particular embodiments of the invention, the PECAM-1 protein, and the gene encoding it, are those of a mammal including a human. Pharmaceutical compositions comprising the antisense compounds of the invention, and various methods of using the antisense compounds of the invention, are also herein provided. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1E show the sequence of a cDNA encoding human PECAM-1 (SEQ ID NO: 1; Genbank Accession No. M28526, locus name "HUMPECAM1") and the locations and sequences of antisense oligonucleotides described in the Examples. The cDNA sequence is written from 5' to 3 ' and has vertical marks indicating every 10th base; the cumulative number of bases in the sequence is given in bold to the right of each line. The start (ATG) and stop (TAG) codons are emboldened and double- underlined. The nucleotide base sequences of the antisense oligonucleotides are written from 3' to 5 ' to demonstrate their complementary nature, and their ISIS number is given in parentheses to the right of each line. Figure 2 shows a portion of the sequence of the stop codon region of a cDNA encoding human PECAM-1 (bases 2305-2394 of SEQ ID NO: 1; GenBank Accession No. M28526, locus name "HUMPECAM1") and the locations and sequences of various antisense oligonucleotides described in the Examples . The cDNA sequence is written from 3 1 to 5 ' , base 2350 is indicated by a vertical mark, and the stop codon is emboldened and underlined. The nucleotide base sequences of the antisense oligonucleotides are written from 5' to 3 ' . Figure 3 shows a portion of the sequence of the 3' untranslated region of a cDNA encoding human PECAM-1 (bases 2436-2520 of SEQ ID NO: 1) and the locations and sequences of various antisense oligonucleotides described in the Examples. The cDNA sequence is written from 3' to 5' and bases 2450 and 2500 are indicated by vertical marks. The nucleotide base sequences of the antisense oligonucleotides are written from 5' to 3' . DETAILED DESCRIPTION OF THE INVENTION Oligonucleotides may comprise nucleotide sequences sufficient in identity and number to effect specific hybridization with a particular nucleic acid. Such oligonucleotides are commonly described as "antisense." - 10 - Antisense oligonucleotides are commonly used as research reagents, diagnostic aids, and therapeutic agents. It has been discovered that genes encoding platelet endothelial cell adhesion molecule-1 (PECAM-1; also known as CD31 antigen or endoCAM) proteins, including human PECAM-1, are particularly amenable to this approach. More specifically, the present invention is directed to antisense compounds, including oligonucleotides, that modulate the expression of PECAM-1. Methods of modulating the expression of PECAM-1 proteins with antisense compounds are provided herein and are believed to be useful both therapeutically and diagnostically as a consequence of the association between PECAM-1 expression and certain hyperproliferative and inflammatory disorders. These methods are also useful as tools, for example, in the detection and determination of the role of PECAM-1 in various cell functions and physiological processes and conditions, and for the diagnosis of conditions associated with such expression and activation. As a consequence of the association between PECAM-1 and normal and abnormal cell-cell interactions, inhibition of the expression of PECAM-1 proteins is expected to lead to, for example, the inhibition of a variety of inflammatory events and tumorigenic and/or metastatic events and, accordingly, results in modulation of the undesirable consequences of such events. Such modulation is desirable for treating (i.e., providing prophylactic, palliative and/or therapeutic effects) various inflammatory and hyperproliferative disorders or diseases. Such inhibition of PECAM-1, and other CAMs, is further desirable for preventing or modulating the development of such diseases or disorders in an animal suspected of being, or known to be, prone to such diseases or disorders. The present invention also comprises methods of inhibiting a variety of PECAM-1-mediated inflammatory and - 11 - tumorigenic and/or metastatic events using the antisense compounds of the invention. Methods of treating conditions m which abnormal or excessive PECAM-1 expression and/or PECAM-1-medιated inflammation occurs are also provided. These methods employ the antisense compounds of the invention and are believed to be useful both therapeutically and as clinical research and diagnostic tools. The oligonucleotides of the present invention may also be used for research purposes. Thus, the specific hybridization exhibited by the oligonucleotides of the present invention may be used for assays, purifications, cellular product preparations and in other methodologies which may be appreciated by persons of ordinary skill m the art. The present invention employs antisense compounds which modulate the function of DNA or messenger RNA (mRNA) encoding a protein (PECAM-1) the modulation of which is desired and ultimately regulate the expression of the protein. Hybridization of an antisense oligonucleotide with its mRNA target interferes with the normal role of mRNA and causes a modulation of its function m cells. The functions of mRNA to be interfered with include all vital functions such as translocation of the RNA to the site for protein translation, actual translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and possibly even independent catalytic activity which may be engaged in by the RNA. The overall effect of such interference with mRNA function is modulation of the expression of a protein, wherein "modulation" means either an increase (stimulation) or a decrease (inhibition) m the expression of the protein. In the context of the present invention, inhibition is the preferred form of modulation of gene expression. It is preferred to target specific genes for antisense attack. "Targeting" an oligonucleotide to the associated - 12 - nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a foreign nucleic acid from an infectious agent. In the present invention, the target is a cellular gene associated with hyperproliferative disorders. The targeting process also includes determination of a site or sites within this gene for the oligonucleotide interaction to occur such that the desired effect, either detection or modulation of expression of the protein, will result. Once the target site or sites have been identified, oligonucleotides are chosen which are sufficiently complementary to the target, i.e., hybridize sufficiently well and with sufficient specificity to give the desired effect. Generally, there are several regions of a gene that may be targeted for antisense modulation: the 5' "cap," which comprises an N7-methylated guanosine residue joined to the most 5' residue of the mRNA via a triphosphate linkage (Baker, Chapter 3 In : An tisense Research and Applica tions , Crooke et al . , eds., CRC Press, Boca Raton, FL, 1993, pages 37-53); the 5' untranslated region (hereinafter, the "5'-UTR"), the translation initiation codon region (hereinafter, the "AUG" region), the open reading frame (hereinafter, the "ORF") or "coding region, " the translation termination codon region (hereinafter, the "stop codon" region or simply "stop" for short) and the 3' untranslated region (hereinafter, the "3'- UTR") . As is known in the art, these regions are arranged in a typical messenger RNA molecule in the following order (left to right, 5' to 3'): cap, 5 ' -UTR, AUG, ORF, stop codon, 3'- UTR. As is known in the art, although some eukaryotic transcripts are directly translated, many ORFs contain one or - 13 - more sequences, known as "introns," which are excised from a transcript before it is translated; the expressed (unexcised) portions of the ORF are referred to as "exons" (Alberts et al . , Molecular Biology of the Cell , 1983, Garland Publishing Inc., New York, pp. 411-415) . Furthermore, because many eukaryotic ORFs are a thousand nucleotides or more in length, it is often convenient to subdivide the ORF into, e.g., the 5' ORF region, the central ORF region, and the 3' ORF region. In some instances, an ORF contains one or more sites that may be targeted due to some functional significance in vivo . Examples of the latter types of sites include intragenic stem- loop structures (see, e.g., U.S. Patent No. 5,512,438) and, in unprocessed mRNA molecules, intron/exon splice sites. Within the context of the present invention, one preferred intragenic site is the region encompassing the translation initiation codon of the open reading frame (ORF) of the gene. Because, as is known in the art, the translation initiation codon is typically 5 ' -AUG (in transcribed mRNA molecules; 5 ' -ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the "AUG codon," the "start codon" or the "AUG start codon." A minority of genes have a translation initiation codon having the RNA sequence 5'-GUG, 5 ' -UUG or 5'-CUG, and 5'-AUA, 5 ' -ACG and 5 ' -CUG have been shown to function in vivo . Furthermore, 5 ' -UUU functions as a translation initiation codon in vi tro (Brigstock et al . , Growth Factors, 1990, 4 , 45; Gelbert et al . , Somat . Cell . Mol . Genet . , 1990, 1 6, 173; Gold and Stormo, in: Escherichia coli and Salmonella typhimurium : Cell ular and Molecular Biology, Vol. 2, 1987, Neidhardt et al . , eds., American Society for Microbiology, Washington, D.C., p. 1303 . Thus, the terms "translation initiation codon" and "start codon" can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine - 14 - (in eukaryotes) or formylmethionine (prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions, in order to generate related polypeptides having different amino terminal sequences. In the context of the invention, "start codon" and "translation initiation codon" refer to the codon or codons that are used in vivo to initiate translation of an mRNA molecule transcribed from a gene encoding a PECAM-1 protein, regardless of the nucleotide sequence (s) of such codons. It is also known in the art that a translation termination codon (or "stop codon") of a gene may have one of three sequences, i.e., 5 ' -UAA, 5 ' -UAG and 5'- UGA (the corresponding DNA sequences are 5'-TAA, 5 ' -TAG and 5'-TGA, respectively) . The terms "start codon region" and "translation initiation region" refer to a portion of such an mRNA or gene that encompasses about 50 contiguous (adjacent) nucleotides in either direction (i.e., 5' or 3') from a translation initiation codon. Similarly, the terms "stop codon region" and "translation termination region" refer to a portion of such an mRNA or gene that encompasses about 50 contiguous (adjacent) nucleotides in either direction (i.e., 5' or 3 ' ) from a translation termination codon. The remainder of the Detailed Description relates in more detail the (1) Antisense Compounds of the Invention and (2) Bioequivalents and (3) Exemplary Utilities thereof, as well as (4) Pharmaceutical Compositions comprising the Antisense Compounds of the Invention and (5) Methods of Administration thereof. 1. Antisense Compounds of the Invention: The present invention employs antisense compounds that modulate PECAM-1 proteins. The term "antisense compounds" (a) specifically - 15 - includes synthetic oligonucleotides, as well as peptide nucleic acids (PNAs), having a nucleobase sequence specifically hybridizable with a nucleic acid encoding a PECAM-1 protein and (b) specifically excludes ribozymes and nucleic acids of biological origin. In the context of this invention, the term "oligonucleotide" refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent intersugar (backbone) linkages as well as oligonucleotides having non-naturally-occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target and increased stability in the presence of nucleases. The antisense compounds of the invention are synthesized in vitro and do not include antisense compositions of biological origin, or genetic vector constructs designed to direct the in vivo synthesis of antisense molecules. The antisense compounds in accordance with this invention preferably comprise from about 8 to about 30 nucleobases, more preferably from about 12 to about 28 and most preferably from about 20 to about 26 nucleobases. Particularly preferred antisense compounds are antisense oligonucleotides. A discussion of antisense oligonucleotides and some desirable modifications can be found in De Mesmaeker et al . , Ace . Chem . Res . , 1995, 28, 366. An oligonucleotide is a polymer of a repeating unit generically known as a nucleotide. An unmodified (naturally occurring) nucleotide has three components: (1) a nitrogen- containing heterocyclic base linked by one of its nitrogen atoms to (2) a 5-pentofuranosyl sugar and (3) a phosphate - 16 - esterified to one of the 5' or 3' carbon atoms of the sugar. When incorporated into an oligonucleotide chain, the phosphate of a first nucleotide is also esterified to an adjacent sugar of a second, adjacent nucleotide via a 3 '-5' phosphate linkage. As is known in the art, a nucleoside is a base-sugar combination. The base portion of the nucleoside is normally a heterocyclic base. The two most common classes of such heterocyclic bases are the purines and the pyrimidines . Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to either the 2', 3' or 5' hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. The respective ends of this linear polymeric structure can be further joined to form a circular structure, however, within the context of the invention, open linear structures are generally preferred. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the intersugar "backbone" of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3' to 5' phosphodiester linkage. The backbone of an oligonucleotide (or other antisense compound) positions a series of bases in a specific order; the written representation of this ordered series of bases, usually written in 5 ' to 3 ' order unless otherwise indicated, is known as a nucleotide or nucleobase sequence. Oligonucleotides may comprise nucleotide sequences sufficient in identity and number to effect specific hybridization with a particular nucleic acid. Such oligonucleotides which specifically hybridize to a portion of - 17 - the sense strand of a gene are commonly described as "antisense." In the context of the invention, "hybridization" means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleotides. For example, adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bonds. "Complementary," as used herein, refers to the capacity for precise pairing between two nucleotides. For example, if a nucleotide at a certain position of an oligonucleotide is capable of hydrogen bonding with a nucleotide at the same position of a DNA or RNA molecule, then the oligonucleotide and the DNA or RNA are considered to be complementary to each other at that position. The oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides which can hydrogen bond with each other. "Specifically hybridizable" and "complementary" are thus terms which are used to indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between the oligonucleotide and the DNA or RNA target. An oligonucleotide is specifically hybridizable to its target sequence due to the formation of base pairs between specific partner nucleobases in the interior of a nucleic acid duplex. Among the naturally occurring nucleobases, guanine (G) binds to cytosine (C) , and adenine (A) binds to thymine (T) or uracil (U) . In addition to the equivalency of U (RNA) and T (DNA) as partners for A, other naturally occurring nucleobase equivalents are known, including 5-methylcytosine and 5-hydroxymethylcytosine (HMC) (C equivalents), and 5-hydroxymethyluracil (U equivalent) . Furthermore, synthetic nucleobases which retain partner specificity are known in the art and include, for example, 7- - 18 - deaza-Guanme, which retains partner specificity for C. Thus, an oligonucleotide' s capacity to specifically hybridize with its target sequence will not be altered by a chemical modification to a nucleobase m the nucleotide sequence of the oligonucleotide which does not impact its specificity for a partner nucleobase in the target nucleic ac d. It is understood m the art that the nucleobase sequence of an oligonucleotide or other antisense compound need not be 100% complementary to its target nucleic acid sequence to be specifically hybridizable. An antisense compound is specifically hybridizable to its target nucleic acid when there is a sufficient degree of complementarity to avoid nonspecific binding of the oligonucleotide to non-target sequences under conditions in which specific binding is desired, i . e . , under physiological conditions m the case of in vivo assays or therapeutic treatment, or, m the case of m vi tro assays, under assay conditions. Antisense oligonucleotides are commonly used as research reagents, diagnostic aids, and therapeutic agents. For example, antisense oligonucleotides, which are able to inhibit gene expression with exquisite specificity, are often used by those of ordinary skill to elucidate the function of particular genes, for example to distinguish between the functions of various members of a biological pathway. This specific inhibitory effect has, therefore, been harnessed by those skilled m the art for research uses. The specificity and sensitivity of oligonucleotides is also harnessed by those of skill in the art for therapeutic uses. Specific examples of preferred antisense compounds useful in this invention include oligonucleotides containing modified backbones or non- natural intersugar linkages. As defined m this specification, oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone 19 and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their intersugar backbone can also be considered to be oligonucleosides . Specific oligonucleotide chemical modifications are described in the following subsections. It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the following modifications may be incorporated in a single antisense compound or even in a single residue thereof, for example, at a single nucleoside within an oligonucleotide. A. Modified Linkages: Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphoro- dithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3' -amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thiono- alkylphosphonates, thionoalklyphosphotriesters, and borano- phosphates having normal 3' -5' linkages, 2' -5' linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3' -5' to 5' -3' or 2' -5' to 5' -2' . Various salts, mixed salts and free acid forms are also included. Representative United States Patents that teach the preparation of the above phosphorus atom containing linkages include, but are not limited to, U.S. Patents Nos. 3,687,808; 4,469,863 4,476,301 5,023,243 5,177,196 5,188,897 5,264,423 5,276,019 5,278,302 5,286,717 5,321,131 5,399,676 5,405,939 5,453,496 5,455,233 5,466,677 5,476,925 5,519,126 5,536, 821 5,541,306 5,550,111 20 5,563,253; 5,571,799; 5,587,361; 5,625,050; and 5,697,248, certain of which are commonly owned with this application, and each of which is herein incorporated by reference. Preferred modified oligonucleotide backbones that do not include a phosphorus atom therein (i.e., oligonucleosides) have backbones that are formed by short chain alkyl or cycloalkyl intersugar linkages, mixed heteroatom and alkyl or cycloalkyl intersugar linkages, or one or more short chain heteroatomic or heterocyclic intersugar linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, 0, S and CH 2 component parts . Representative United States patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Patents Nos. 5,034,506; 5,166,315; 5,185,444 5,214,134 5,216,141; 5,235,033; 5,264,562; 5,264,564 5,405, 938 5,434,257; 5,466,677; 5,470,967; 5,489,677 5,541,307 5,561,225; 5,596,086; 5,602,240; 5,610,289 5,602,240 5,608,046; 5,610,289; 5,618,704; 5,623,070 5, 663,312 5,633,360; 5,677,437; and 5,677,439, certain of which are commonly owned with this application, and each of which is herein incorporated by reference. In other preferred oligonucleotide mimetics, both the sugar and the intersugar linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups . The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, - 21 - an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA) . In PNA compounds, the sugar- backbone of an oligonucleotide is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Patents Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al . , Science, 1991, 254 , 1497. Most preferred embodiments of the invention are oligonucleotides with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular -CH 2 -NH-0-CH 2 -, -CH 2 -N (CH 3 ) -0-CH 2 - [known as a methylene (methylimino) or MMI backbone] , -CH 2 -0-N (CH 3 ) -CH 2 -, - CH 2 -N (CH 3 ) - N(CH 3 )-CH 2 - and -0-N (CH 3 ) -CH 2 -CH 2 - [wherein the native phosphodiester backbone is represented as -0-P-0-CH 2 -] of the above referenced U.S. Patent 5,489,677, and the amide backbones of the above referenced U.S. Patent No. 5,602,240. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Patent No. 5,034,506. B. Modified Nucleobases: The compounds of the invention may additionally or alternatively comprise nucleobase (often referred to in the art simply as "base") modifications or substitutions. As used herein, "unmodified" or "natural" nucleobases include the purine bases adenine (A) and guanine (G) , and the pyrimidine bases thymine (T) , cytosine (C) and uracil (U) . Modified nucleobases include other synthetic and natural nucleobases such as 5- methylcytosine (5-me-C) , 5-hydroxymethyl cytosine, xanthine, - 22 - hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2- thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5- propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil) , 4-thiouracil, 8-halo, 8- amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8- substituted adenines and guanines, 5-halo particularly 5- bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3- deazaguanine and 3-deazaadenine . Further nucleobases include those disclosed in United States Patent No. 3,687,808, those disclosed in the Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J.I., ed. John Wiley & Sons, 1990, those disclosed by Englisch et al . , Angewandte Chemie, Interna tional Edi tion, 1991, 30, 613, and those disclosed by Sanghvi, Y.S., Chapter 15, Antisense Research and Applica tions, pages 289-302, Crooke, S.T. and Lebleu, B., ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5- substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5- propynyluracil and 5-propynylcytosine . 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2°C { Id. , pages 276-278) and are presently preferred base substitutions, even more particularly when combined with 2 ' -methoxyethyl sugar modifications. Representative United States patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Patent 3,687,808, as well as - 23 - U.S. Patents 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; and 5,681,941, certain of which are commonly owned, and each of which is herein incorporated by reference, and commonly owned United States patent application 08/762,488, filed on December 10, 1996, also herein incorporated by reference. C. Sugar Modifications: The antisense compounds of the invention may additionally or alternatively comprise one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following at the 2 ' position: OH; F; 0-, S-, or N-alkyl, 0-, S-, or N-alkenyl, or 0, S- or N-alkynyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted λ to C 10 alkyl or C 2 to C 10 alkenyl and alkynyl. Particularly preferred are 0[ (CH 2 ) n O] m CH 3 , 0(CH 2 ) n OCH 3 , 0(CH 2 ) n NH 2; 0 (CH 2 ) n CH 3, 0 (CH,) n 0NH 2/ and 0(CH 2 ) n ON[ (CH 2 ) n CH 3 ) ] 2 ι where n and m are from 1 to about 10. Other preferred oligonucleotides comprise one of the following at the 2' position: C x to C 10 lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3, OCF 3 _ SOCH 3ι S0 2 CH 3; ON0 2; N0 2; N 3> NH 2j heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, poly- alkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2'- methoxyethoxy [2 ' -0-CH 2 CH QCH , 3 also known as 2'-0-(2- methoxyethyl) or 2 '-MOE] (Martin et al . , Helv. Chim . Acta , 1995, 78, 486), i.e., an alkoxyalkoxy group. A further preferred modification includes 2' -dimethylaminooxyethoxy, - 24 i.e., a 0 (CH 2 ) 2 ON (CH 3 ) group, also known as 2'-DMAOE, as described in co-owned United States patent application Serial Number 09/016,520, filed on January 30, 1998, the contents of which are herein incorporated by reference. Other preferred modifications include 2 ' -methoxy (2'- O-CH 3 ) , 2 ' -aminopropoxy (2 ' -OCH, CH CI| N^ ) and 2'-fluoro (2'-F). Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3' position of the sugar on the 3' terminal nucleotide or in 2' -5' linked oligonucleotides and the 5' position of 5' terminal nucleotide. Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugars structures include, but are not limited to, U.S. Patents Nos. 4,981,957; 5,118,800 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722 5,597,909; 5,610,300; 5,627,0531 5,639,873; 5,646,265 5,658,873; 5,670,633; and 5,700,920, certain of which are commonly owned, and each of which is herein incorporated by reference, and commonly owned United States patent application 08/468,037, filed on June 5, 1995, also herein incorporated by reference. D. Other Modifications: Additional modifications may also be made at other positions on the oligonucleotide, particularly the 3' position of the sugar on the 3' terminal nucleotide and the 5' position of 5' terminal nucleotide. For example, one additional modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety 25 (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765), a thiocholesterol (Oberhauser et al . , Nucl. Acids Res., 1992, 20, 533), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J. , 1991, 10, 111; Kabanov et al., FEBS Lett., 1990, 259, 327; Svinarchuk et al., Biochimie, 1993, 75, 49), a phospholipid, e.g., di-hexadecyl- rac-glycerol or triethylammonium 1, 2-di-O-hexadecyl-rac- glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651; Shea et al., Nucl. Acids Res., 1990, 18, 3777), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923). Representative United States patents that teach the preparation of such oligonucleotide conjugates include, but are not limited to, U.S. Patents Nos. 4,828,979; 4,948,882 5,218,105 5,525,465 5,541,313 5,545,730 5,552,538 5,578,717 5,580,731 5,580,731 5,591,584 5,109,124 5,118,802 5.138.045 5,414,077 5,486, 603 5,512,439 5,578,718 5.608.046 4,587,044 4,605,735 4, 667,025 4,762,779 4,789,737 4,824, 941 4,835,263 4,876,335 4,904,582 4,958,013 5,082,830 5,112, 963 5,214, 136 5,082,830 5,112, 963 5,214, 136 5,245,022 5,254,469 5,258,506 5,262,536 5,272,250 5,292, 873 5,317,098 5,371,241 5,391,723 5, 416,203 5, 451,463 5, 510,475 5,512, 667 5,514,785 5,565,552 5,567, 810 5, 574,142 - 26 - 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941, certain of which are commonly owned, and each of which is herein incorporated by reference. E. Chimeric Oligonucleotides: The present invention also includes antisense compounds which are chimeric compounds. "Chimeric" antisense compounds or "chimeras," in the context of this invention, are antisense compounds, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for enzymes capable of cleaving RNA: DNA or RNA: RNA hybrids. By way of example, RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA: DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide inhibition of gene expression. Consequently, comparable results can often be obtained with shorter oligonucleotides when chimeric oligonucleotides are used, compared to phosphorothioate deoxyoligonucleotides hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art. RNase H-mediated target cleavage is distinct from the use of ribozymes to cleave nucleic acids, and ribozymes are not comprehended by the present invention. By way of example, such "chimeras" may be "gapmers," i.e., oligonucleotides in which a central portion (the "gap") - 27 - of the oligonucleotide serves as a substrate for, e.g., RNase H, and the 5' and 3' portions (the "wings") are modified in such a fashion so as to have greater affinity for, or stability when duplexed with, the target RNA molecule but are unable to support nuclease activity (e.g., 2 ' -fluoro- or 2'- methoxyethoxy- substituted) . Other chimeras include "hemimers," that is, oligonucleotides in which the 5' portion of the oligonucleotide serves as a substrate for, e.g., RNase H, whereas the 3' portion is modified in such a fashion so as to have greater affinity for, or stability when duplexed with, the target RNA molecule but is unable to support nuclease activity (e.g., 2 ' -fluoro- or 2 ' -methoxyethoxy- substituted), or vice-versa . A number of chemical modifications to oligonucleotides that confer greater oligonucleotide : RNA duplex stability have been described by Freier et al . { Nucl . Acids Res . , 1997, 25, 4429) . Such modifications are preferred for the RNase H- refractory portions of chimeric oligonucleotides and may generally be used to enhance the affinity of an antisense compound for a target RNA. Chimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers . Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Patents Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, certain of which are commonly owned, and each of which is herein incorporated by reference, and commonly owned and allowed - 28 - United States patent application serial number 08/465,880, filed on June 6, 1995, also herein incorporated by reference. F. Synthesis: The oligonucleotides used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, CA) . Any other means for such synthesis known in the art may additionally or alternatively be employed. It is also known to use similar techniques to prepare other oligonucleotides such as the phosphorothioates and alkylated derivatives . 1. Teachings regarding the synthesis of particular modified oligonucleotides may be found in the following U.S. patents or pending patent applications, each of which is commonly assigned with this application: U.S. Patents Nos. 5,138,045 and 5,218,105, drawn to polyamine conjugated oligonucleotides; U.S. Patent No. 5,212,295, drawn to monomers for the preparation of oligonucleotides having chiral phosphorus linkages; U.S. Patents Nos. 5,378,825 and 5,541,307, drawn to oligonucleotides having modified backbones; U.S. Patent No. 5,386,023, drawn to backbone modified oligonucleotides and the preparation thereof through reductive coupling; U.S. Patent No. 5,457,191, drawn to modified nucleobases based on the 3-deazapurine ring system and methods of synthesis thereof; U.S. Patent No. 5,459,255, drawn to modified nucleobases based on N-2 substituted purines; U.S. Patent No. 5,521,302, drawn to processes for preparing oligonucleotides having chiral phosphorus linkages; U.S. Patent No. 5,539,082, drawn to peptide nucleic acids; U.S. Patent No. 5,554,746, drawn to oligonucleotides having β-lactam backbones; U.S. Patent No. 5,571,902, drawn to methods and materials for the synthesis of oligonucleotides; - 29 - U.S. Patent No. 5,578,718, drawn to nucleosides having alkylthio groups, wherein such groups may be used as linkers to other moieties attached at any of a variety of positions of the nucleoside; U.S. Patents Nos. 5,587,361 and 5,599,797, drawn to oligonucleotides having phosphorothioate linkages of high chiral purity; U.S. Patent No. 5,506,351, drawn to processes for the preparation of 2'-0-alkyl guanosine and related compounds, including 2, 6-diaminopurine compounds; U.S. Patent No. 5,587,469, drawn to oligonucleotides having N-2 substituted purines; U.S. Patent No. 5,587,470, drawn to oligonucleotides having 3-deazapurines; U.S. Patents Nos. 5,223,168, issued June 29, 1993, and 5,608,046, both drawn to conjugated 4'-desmethyl nucleoside analogs; U.S. Patent Nos. 5,602,240, and 5,610,289, drawn to backbone modified oligonucleotide analogs; and U.S. patent application Serial No. 08/383,666, filed February 3, 1995, and U.S. Patent No. 5,459,255, drawn to, inter alia , methods of synthesizing 2'- fluoro-oligonucleotides . 2. Bioejuivalents : The compounds of the invention encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to "prodrugs" and "pharmaceutically acceptable salts" of the antisense compounds of the invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents . A. Oligonucleotide Prodrugs : The antisense compounds of the invention may additionally or alternatively be prepared to be delivered in a "prodrug" form. The term "prodrug" indicates a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., - 30 - drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions . In particular, prodrug versions of the antisense compounds of the invention are prepared as SATE [ (S-acetyl-2-thioethyl) phosphate] derivatives according to the methods disclosed in WO 93/24510 to Gosselin et al . , published December 9, 1993. B. Pharmaceutically Acceptable Salts: The term "pharmaceutically acceptable salts" refers to physiologically and pharmaceutically acceptable salts of the antisense compounds of the invention: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto. Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are chloroprocaine, choline, N, N ' -dibenzylethylenediamine, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al . , "Pharmaceutical Salts," J. of Pharma Sci . , 1977, 66: 1 ) . The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. As used herein, a "pharmaceutical addition salt" includes a pharmaceutically acceptable salt of an acid form of one of the components of the compositions of the invention. - 31 - These include organic or inorganic acid salts of the amines. Preferred acid salts are the hydrochlorides, acetates, salicylates, nitrates and phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of a variety of inorganic and organic acids, such as, for example, with inorganic acids, such as for example hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, embonic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, nicotinic acid, isonicotinic acid or 2-acetoxybenzoic acid; and with amino acids, such as the 20 alpha-amino acids involved in the synthesis of proteins in nature, for example glutamic acid or aspartic acid, and also with naphthalene-1, 5-disulfonic acid, phenylacetic acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamates), or with other acid organic compounds, such as ascorbic acid. Pharmaceutically acceptable salts of compounds may also be prepared with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or hydrogen carbonates are also possible . - 32 - For oligonucleotides, preferred examples of pharmaceutically acceptable salts include but are not limited to (a) salts formed with cations such as sodium, potassium, ammonium, magnesium, calcium, polyamines such as sper ine and spermidine, etc . ; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (d) salts formed from elemental anions such as chlorine, bromine, and iodine. 3. Exemplary Utilities of the Invention: The oligonucleotides of the present invention specifically hybridize to nucleic acids (e.g., mRNAs) encoding a PECAM-1 protein. The antisense compounds of the present invention can be utilized as therapeutic compounds, as diagnostic tools or research reagents that can be incorporated into kits as well as other methodologies as will be apparent to persons of ordinary skill in the art. A. Assays and Diagnostic Applications: The oligonucleotides of the present invention can be used to detect the presence of PECAM-1 protein-specific nucleic acids in a cell or tissue sample. For example, radiolabeled oligonucleotides can be prepared by 32 P labeling at the 5' end with polynucleotide kinase. (Sambrook et al . , Molecular Cloning. A Labora tory Manual , Cold Spring Harbor Laboratory Press, 1989, Volume 2, pg. 10.59.) Radiolabeled oligonucleotides are then contacted with cell or tissue - 33 - samples suspected of containing PECAM-1 protein message RNAs (and thus PECAM-1 proteins), and the samples are washed to remove unbound oligonucleotide. Radioactivity remaining in the sample indicates the presence of bound oligonucleotide, which in turn indicates the presence of nucleic acids complementary to the oligonucleotide, and can be quantitated using a scintillation counter or other routine means. Expression of nucleic acids encoding these proteins is thus detected. Radiolabeled oligonucleotides of the present invention can also be used to perform autoradiography of tissues to determine the localization, distribution and quantitation of PECAM-1 proteins for research, diagnostic or therapeutic purposes. In such studies, tissue sections are treated with radiolabeled oligonucleotide and washed as described above, then exposed to photographic emulsion according to routine autoradiography procedures. The emulsion, when developed, yields an image of silver grains over the regions expressing a PECAM-1 protein gene. Quantitation of the silver grains permits detection of the expression of mRNA molecules encoding these proteins and permits targeting of oligonucleotides to these areas . Analogous assays for fluorescent detection of expression of PECAM-1 protein nucleic acids can be developed using oligonucleotides of the present invention which are conjugated with fluorescein or other fluorescent tags instead of radiolabeling . Such conjugations are routinely accomplished during solid phase synthesis using fluorescently-labeled amidites or controlled pore glass (CPG) columns. Fluorescein- labeled amidites and CPG are available from, e . g. , Glen Research, Sterling VA. Other means of labeling oligonucleotides are known in the art (see, e . g. , Ruth, Chapter 6 In : Methods in Molecular Biology, Vol . 26: Protocols - 34 - for Oligonucleotide Conj uga tes, Agrawal, ed., Humana Press Inc., Totowa, NJ, 1994, pages 167-185). Kits for detecting the presence or absence of expression of a PECAM-1 protein may also be prepared. Such kits include an oligonucleotide targeted to an appropriate gene, i . e . , a gene encoding a PECAM-1 protein. Appropriate kit and assay formats, such as, e.g., "sandwich" assays, are known in the art and can easily be adapted for use with the antisense compounds of the invention. Hybridization of the antisense compounds of the invention with a nucleic acid encoding a PECAM-1 protein can be detected by means known in the art. Such means may include conjugation of an enzyme to the oligonucleotide, radiolabelling of the oligonucleotide or any other suitable detection systems. B. Biologically Active Oligonucleotides: The invention is also drawn to the administration of oligonucleotides having biological activity to cultured cells, isolated tissues and organs and animals. By "having biological activity, " it is meant that the oligonucleotide functions to modulate the expression of one or more genes in cultured cells, isolated tissues or organs and/or animals. Such modulation can be achieved by an antisense oligonucleotide by a variety of mechanisms known in the art, including but not limited to transcriptional arrest; effects on RNA processing (capping, polyadenylation and splicing) and transportation; enhancement of cellular degradation of the target nucleic acid; and translational arrest (Crooke et al . , Exp . Opin . Ther . Pa ten ts, 1996, 6:855) . In an animal other than a human, the compositions and methods of the invention can be used to study the function of one or more genes in the animal. For example, antisense oligonucleotides have been systemically administered to rats in order to study the role of the Λf-methyl-D-aspartate - 35 - receptor in neuronal death, to mice in order to investigate the biological role of protein kinase C-α, and to rats in order to examine the role of the neuropeptide Yl receptor in anxiety (Wahlestedt et al . , Na ture, 1993, 363 : 260 ; Dean et a l . , Proc . Na tl . Acad. Sci . U. S . A. , 1994, 91:11762; and Wahlestedt et al . , Science, 1993, 259:528, respectively). In instances where complex families of related proteins are being investigated, "antisense knockouts" (i.e., inhibition of a gene by systemic administration of antisense oligonucleotides) may represent the most accurate means for examining a specific member of the family (see, generally, Albert et al . , Trends Pharmacol . Sci . , 1994, 15:250). The compositions and methods of the invention also have therapeutic uses in an animal, including a human, having (i.e., suffering from), or known to be or suspected of being prone to having, a disease or disorder that is treatable in whole or in part with one or more nucleic acids. The term "therapeutic uses" is intended to encompass prophylactic, palliative and curative uses wherein the antisense compounds of the invention are contacted with animal cells either in vivo or ex vivo . When contacted with animal cells ex vivo, a therapeutic use includes incorporating such cells into an animal after treatment with one or more of the antisense compounds of the invention. For therapeutic uses, an animal suspected of having a disease or disorder which can be treated or prevented by modulating the expression or activity of a PECAM-1 protein is, for example, treated by administering oligonucleotides in accordance with this invention. The antisense compounds of the invention can be utilized in pharmaceutical compositions by adding an effective amount of an oligonucleotide to a suitable pharmaceutically acceptable carrier such as, e.g., a diluent. Workers in the field have identified antisense, - 36 - triplex and other oligonucleotide compositions which are capable of modulating expression of genes implicated in viral, fungal and metabolic diseases. Antisense oligonucleotides have been safely administered to humans and several clinical trials are presently underway. It is thus established that oligonucleotides can be useful therapeutic instrumentalities that can be configured to be useful in treatment regimes for treatment of cells, tissues and animals, especially humans. The following U.S. patents demonstrate palliative, therapeutic and other methods utilizing antisense oligonucleotides. U. S. Patent No. 5,135,917 provides antisense oligonucleotides that inhibit human interleukin-1 receptor expression. U.S. Patent No. 5,098,890 is directed to antisense oligonucleotides complementary to the c-myb oncogene and antisense oligonucleotide therapies for certain cancerous conditions. U.S. Patent No. 5,087,617 provides methods for treating cancer patients with antisense oligonucleotides. U.S. Patent No. 5,166,195 provides oligonucleotide inhibitors of Human Immunodeficiency Virus (HIV). U.S. Patent No. 5,004,810 provides oligomers capable of hybridizing to herpes simplex virus Vmw65 mRNA and inhibiting replication. U.S. Patent No. 5,194,428 provides antisense oligonucleotides naving antiviral activity against influenzavirus . U.S. Patent No. 4,806,463 provides antisense oligonucleotides and methods using them to inhibit HTLV-III replication. U.S. Patent No. 5,286,717 provides oligonucleotides having a complementary base sequence to a portion of an oncogene. U.S. Patent No. 5,276,019 and U.S. Patent No. 5,264,423 are directed to phosphorothioate oligonucleotide analogs used to prevent replication of foreign nucleic acids in cells. U.S. Patent No. 4,689,320 is directed to antisense oligonucleotides as antiviral agents specific to cytomegalovirus (CMV). U.S. Patent No. 5,098,890 provides oligonucleotides complementary to at least a portion of the - 37 - mRNA transcript of the human c-myb gene. U.S. Patent No. 5,242,906 provides antisense oligonucleotides useful in the treatment of latent Epstein-Barr virus (EBV) infections. As used herein, the term "disease or disorder" (1) includes any abnormal condition of an organism or part, especially as a consequence of infection, inherent weakness, environmental stress, that impairs normal physiological functioning; (2) excludes pregnancy per se but not autoimmune and other diseases associated with pregnancy; and (3) includes cancers and tumors. The term "known to be or suspected of being prone to having a disease or disorder" indicates that the subject animal has been determined to be, or is suspected of being, at increased risk, relative to the general population of such animals, of developing a particular disease or disorder as herein defined. For example, a subject animal "known to be or suspected of being prone to having a disease or disorder" could have a personal and/or family medical history that includes frequent occurrences of a particular disease or disorder. As another example, a subject animal "known to be or suspected of being prone to having a disease or disorder" could have had such a susceptibility determined by genetic screening according to techniques known in the art (see, e.g., U.S. Congress, Office of Technology Assessment, Chapter 5 In : Genetic Moni toring and Screening in the Workplace, OTA-BA-455, U.S. Government Printing Office, Washington, D.C., 1990, pages 75-99). The term "a disease or disorder that is treatable in whole or in part with one or more antisense compounds" refers to a disease or disorder, as herein defined, (1) the management, modulation or treatment thereof, and/or (2) therapeutic, curative, palliative and/or prophylactic relief therefrom, can be provided via the administration of compositions comprising one or more antisense compounds of the invention. - 38 - 4. Pha.rmaceutical Compositions Comprising Compounds of the Invention: The present invention provides for therapeutic and pharmaceutical compositions comprising one or more PECAM- 1-modulating antisense compounds. Compositions for the administration of the antisense compounds of the invention may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. A. Compositions for Alimentary Delivery: In a preferred embodiment of the invention, one or more PECAM-1- modulating antisense compounds are administered via alimentary delivery, preferably by oral administration. Pharmaceutical compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, troches, tablets or SECs (soft elastic capsules or "caplets") . Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids, carrier substances or binders may be added to such compositions. Such pharmaceutical compositions have the effect of delivering the antisense compound (s) to the alimentary canal for exposure to the mucosa thereof. Accordingly, the pharmaceutical composition can comprise material effective in protecting the oligonucleotide from pH extremes of the stomach, or in releasing the oligonucleotide over time, to optimize the delivery thereof to a particular mucosal site. Enteric coatings for acid-resistant tablets, capsules and caplets are known in the art and typically include acetate phthalate, propylene glycol and sorbitan monoleate. Various methods for producing pharmaceutical compositions for alimentary delivery are well known in the art. See, generally, Nairn, Chapter 83; Block, Chapter 87; Rudnic et al . , Chapter 89; Porter, Chapter 90; and Longer et al . , Chapter 91 In : Remington ' s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990. - 39 - The antisense compounds of the invention can be incorporated in a known manner into customary pharmaceutical compositions, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers (excipients) . The therapeutically active compound should in each case be present here in a concentration of about 0.5% to about 95% by weight of the total mixture, i.e., in amounts which are sufficient to achieve the stated dosage range. The pharmaceutical compositions are prepared, for example, by diluting the active compounds with pharmaceutically acceptable carriers, if appropriate using emulsifying agents and/or dispersing agents, and, for example, in the case where water is used as the diluent, organic solvents can be used as auxiliary solvents if appropriate. Pharmaceutical compositions may be formulated in a conventional manner using additional pharmaceutically acceptable carriers as appropriate. Thus, the compositions may be prepared by conventional means with additional excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) ; fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrates (e.g., starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate) . Tablets are coated by methods well known in the art and may also contain flavoring, coloring and/or sweetening agents. Compositions comprising one or more PECAM-1-modulating antisense compounds can be administered via the rectal mode. In particular, therapeutic or pharmaceutical compositions for rectal administration include foams, solutions (enemas) and suppositories. Rectal suppositories for adults are usually - 40 - tapered at one or both ends and typically weigh about 2 g each, with infant rectal suppositories typically weighing about one-half as much when the usual base, cocoa butter, is used (Block, Chapter 87 In : Remington ' s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990) . The pharmaceutical compositions, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredient (s) with the pharmaceutically acceptable carrier (s). In general the pharmaceutical compositions are prepared by uniformly and intimately bringing into association the active ingredient (s ) with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing predetermined amounts of the active ingredients; as powders or granules; as solutions or suspensions in an aqueous liquid or a non-aqueous liquid; or as oil-m-water emulsions or water-m-oil liquid emulsions . A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing m a suitable machine, the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding m a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the - 41 - active ingredients therein. Sustained release oral delivery systems and/or enteric coatings for orally administered dosage forms are described m U.S. Patents Nos. 4,704,295; 4,556,552; 4,309,406; and 4,309,404. B. Additives: Pharmaceutical and therapeutic compositions comprising one or more of the antisense compounds of the invention may further include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic carrier substances suitable for non-parenteral administration which do not deleteπously react with the antisense compounds can be used. The pharmaceutical compositions can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings flavorings and/or aromatic substances and the like which do not deleteriously react with the oligonucleotide (s) of the pharmaceutical composition. Pharmaceutical compositions in the form of aqueous suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. Optionally, such compositions may also contain one or more stabilizers, penetration enhancers, carrier compounds or pharmaceutically acceptable carriers. (1) Penetration Enhancers: Pharmaceutical compositions comprising the oligonucleotides of the present invention may also include penetration enhancers in order to enhance the alimentary delivery of the oligonucleotides . Penetration enhancers may be classified as belonging to one of five broad categories, i . e . , fatty acids, bile salts, chelating agents, surfactants and non-surfactants (Lee et al . , Cri tical Reviews in Therapeutic Drug Carrier Systems, 1991, - 42 - 8:91-192; Muranishi, Cri tical Reviews in Therapeuti c Drug Carrier Systems, 1990, 7:1) . Fatty Acids: Various fatty acids and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, recinleate, monoolein (a.k.a. 1- monooleoyl-rac-glycerol) , dilaurin, caprylic acid, arichidonic acid, glyceryl 1-monocaprate, acylcarnitines, acylcholines, l-dodecylazacycloheptan-2-one, mono- and di-glycerides and physiologically acceptable salts thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc . ) (Lee et al . , Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Muranishi, Cri tical Reviews in Therapeutic Drug Carrier Sys tems, 1990, 7:1; El-Hariri et al . , J. Pharm . Pharmacol . , 1992, 44:651). Bile Salts: The physiological roles of bile include the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (Brunton, Chapter 38 In : Goodman & Gilman ' s The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al . , eds., McGraw-Hill, New York, NY, 1996, pages 934-935). Various natural bile salts, and their synthetic derivatives, act as penetration enhancers. Thus, "bile salt" includes any of the naturally occurring components of bile and any of their synthetic derivatives. Chelating Agents: Chelating agents have the added advantage of also serving as DNase inhibitors and include, but are not limited to, citric acid, disodium ethylenediaminetetraacetate (EDTA), salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate) , N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enamines) (Lee et al . , Cri t . Rev. Therap . Drug Carrier Systems , 1991, p. 92; Muranishi, - 43 - Cri t . Rev. Therap . Drug Carrier Systems, 1990, 7, 1; Buur et al . , J. Control Rel . , 1990, 14 , 43). Surfactants: Surfactants include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxyethylene-20-cetyl ether (Lee et al . , Cri tical Reviews in Therapeuti c Drug Carrier Sys tems, 1991, page 92); and perfluorochemical emulsions, such as FC-43 (Takahashi et al . , J. Pharm . Phamacol . , 1988, 40:252). Non-Surfactants : Non-surfactants include, for example, unsaturated cyclic ureas, 1-alkyl- and 1- alkenylazacyclo-alkanone derivatives (Lee et al . , Cri tical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92); and non-steroidal anti-inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al . , J. Pharm . Pharmacol . , 1987, 39:621). (2) Carrier Compounds: As used herein, "carrier compound" refers to a nucleic acid, or analog thereof, which is inert (i.e., does not possess biological activity per se) but is recognized as a nucleic acid by in vivo processes that reduce the bioavailability of a nucleic acid having biological activity by, for example, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction of the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reservoirs, presumably due to competition between the carrier compound and the nucleic acid for a common receptor. For example, the recovery of a partially phosphorothioated oligonucleotide in hepatic tissue is reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4 ' -isothiocyano- stilbene-2 , 2 ' -disulfonic acid (Miyao et al . , An tisense Res . - 44 - Dev. , 1995, 5:115; Takakura et al . , An ti sense & Nucl . Acid Drug Dev. , 1996, 6 : 111 ) . (3) Pha.rmaceutically Acceptable Carriers: In contrast to a carrier compound, a "pharmaceutically acceptable carrier" (excipient) is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The pharmaceutically acceptable carrier may be liquid or solid and is selected with the planned manner of administration in mind so as to provide for the desired bulk, consistency, etc. , when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutically acceptable carriers include, but are not limited to, binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc. ) ; fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc . ) ; lubricants ( e . g. , magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc. ) ; disintegrates (e.g., starch, sodium starch glycolate, etc . ) ; or wetting agents ( e . g. , sodium lauryl sulphate, etc . ) . Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, hydroxymethylcellulose, polyvinylpyrrolidone viscous paraffin and the like. (4) Miscellaneous Additional Components: The compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage - 45 - levels. Thus, for example, the compositions may contain additional compatible pharmaceutically-active materials such as, e.g., antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the composition of present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the invention. C. Colloidal Dispersion Systems: Regardless of the method by which the antisense compounds of the invention are introduced into a patient, colloidal dispersion systems may be used as delivery vehicles to enhance the in vivo stability of the compounds and/or to target the compounds to a particular organ, tissue or cell type. Colloidal dispersion systems include, but are not limited to, macromolecule complexes, nanocapsules, microspheres, beads and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, lipid: oligonucleotide complexes of uncharacterized structure and liposomes . A preferred colloidal dispersion system is a plurality of liposomes. Liposomes are microscopic spheres having an aqueous core surrounded by one or more outer layer (s) made up of lipids arranged in a bilayer configuration (see, generally, Chonn et al . , Current Op . Biotech . , 1995, 6, 698) . The therapeutic potential of liposomes as drug delivery agents was recognized nearly thirty years ago (Sessa et al . , J. Lipid Res . , 1968, 9, 310) . Liposomes, in some instances, may be used as cellular delivery vehicles for bioactive agents in vi tro and in vivo (Mannino et al . , Biotechniques, 1988, 6, 682; Blume et al . , Biochem . et Biophys . Acta , 1990, 1029, 91; Lappalainen et al . , An tiviral Res . , 1994, 23, 119. For - 46 - example, it has been shown that large unilamellar vesicles (LUV) , which range in size from 0.2-0.4 microns, can encapsulate a substantial percentage of an aqueous buffer containing large macromolecules . RNA, DNA and intact virions can be encapsulated within the aqueous interior and delivered to brain cells in a biologically active form (Fraley et al . , Trends Biochem . Sci . , 1981, 6, 11 ) . The targeting of colloidal dispersion systems, including liposomes, can be either passive or active. Passive targeting utilizes the natural tendency of liposomes to distribute to cells of the reticuloendothelial system in organs that contain sinusoidal capillaries. Active targeting, by contrast, involves modification of the liposome by coupling thereto a specific ligand such as a viral protein coat (Morishita et al . , Proc . Na tl . Acad. Sci . (U. S . A . ) , 1993, 90, 8474), monoclonal antibody (or a suitable binding portion thereof) , sugar, glycolipid or protein (or a suitable oligopeptide fragment thereof) , or by changing the composition and/or size of the liposome in order to achieve distribution to organs and cell types other than the naturally occurring sites of localization. The surface of the targeted colloidal dispersion system can be modified in a variety of ways. In the case of a liposomal targeted delivery system, lipid groups can be incorporated into the lipid bilayer of the liposome in order to maintain the targeting ligand in close association with the lipid bilayer. Various linking groups can be used for joining the lipid chains to the targeting ligand. The targeting ligand, which binds a specific cell surface molecule found predominantly on cells to which delivery of the compounds of the invention is desired, may be, for example, (1) a hormone, growth factor or a suitable oligopeptide fragment thereof which is bound by a specific cellular receptor predominantly expressed by cells to which delivery - 47 - is desired or (2) a polyclonal or monoclonal antibody, or a suitable fragment thereof (e.g., Fab; F(ab') 2 ) which specifically binds an antigenic epitope found predominantly on targeted cells. Two or more bioactive agents (e.g., an antisense oligonucleotide and a conventional drug; two oligonucleotides) can be combined within, and delivered by, a single liposome. It is also possible to add agents to colloidal dispersion systems which enhance the intercellular stability and/or targeting of the contents thereof. The liposomes of the invention are formed from vesicle-forming lipids which generally include one or more neutral or negatively charged phospholipids, preferably one or more neutral phospholipids, usually in combination with one or more sterols, particularly cholesterol. Examples of lipids useful in liposome production include phosphatidyl compounds, such as phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, sphingolipids, phosphatidylethanolamine, cerebrosides and gangliosides . Typically, the major lipid component of the liposomes is a phosphatidylcholine (PC) or PC derivative. PC derivatives with a variety of acyl chain groups of varying chain length and degree of saturation are commercially available or may be synthesized by known techniques. For purposes of filter sterilization, less- saturated PCs are generally more easily sized, particularly when the liposomes must be sized below about 0.3 microns. PCs containing saturated fatty acids with carbon chain lengths in the range of C 14 to C 22 , particularly C 16 to C 18 , are preferred, particularly diacyl phosphatidylglycerols . Illustrative phospholipids include, for example, dipalmitoylphosphatidylcholine, phosphatidylcholine and distearoylphosphatidylcholine . Phosphatidylcholines with mono- and di-unsaturated fatty acids and mixtures of saturated and unsaturated fatty acids may also be used. Other suitable - 48 - phospholipids include those with head groups other than choline, such as, for example, ethanolamine, serine, glycerol and inositol. Other suitable lipids include phosphonolipids in which the fatty acids are linked to glycerol via ether linkages rather than ester linkages. Preferred liposomes will include a sterol, e.g., cholesterol, at molar ratios of from about 0.1 to 1.0 (sterol: phospholipid) . Typically, the liposomes of the invention will contain, in their aqueous interiors, one or more antisense oligonucleotides in an amount of from about 0.005 ng/mL to about 400 mg/mL, preferably from about 0.01 ng/mL to about 200 mg/mL, most preferably from about 0.1 ng/mL to about 100 mg/mL, where "about" indicates ± 5% of the desired concentration . Compositions of the invention may include one or more antisense compounds and/or other therapeutic agents entrapped within sterically stabilized liposomes. As used herein, the term "sterically stabilized liposome" refers to a liposome comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome (A) comprises one or more glycolipids, such as monosialoganglioside G M1 , or (B) is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system - 49 - (Allen et al., FEBS Letts., 1987, 223, 42; Wu et al., Cancer Res. , 1993, 53, 3765) . Various liposomes comprising one or more glycolipids are known in the art. Papahadjopoulos et al. {Ann. N.Y. Acad. Sci., 1987, 507, 64) reported the ability of monosialoganglioside G M1 , galactocerebroside sulfate and phosphatidylinositol to improve blood half-lives of liposomes. These findings were expounded upon by Gabizon et al. (Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 6949). U.S. Patent No. 4,837,028 and WO 88/04924, both to Allen et al., disclose liposomes comprising (1) sphingomyelin and (2) the gangliosiαe G M1 or a galactocerebroside sulfate ester. U.S. Patent No. 5,543,152 (Webb et al.) discloses liposomes comprising sphingomyelin. Liposomes comprising 1, 2-sn-dimyristoylphosphatidylcholine are disclosed in WO 97/13499 (Lim et al. ) . Many liposomes comprising lipids derivatized with one or more hydrophilic polymers, and methods of preparation thereof, are known in the art. Sunamoto et al. {Bull. Chem. Soc. Jpn., 1980, 53, 2778) described liposomes comprising a nonionic detergent, 2C 12 15G, that contains a PEG moiety. Ilium et al. (FEBS Letters, 1984, 167, 79) noted that hydrophilic coating of polystyrene particles with polymeric glycols results in significantly enhanced blood half-lives. Synthetic phospholipids modified by the attachment of carboxylic groups of polyalkylene glycols (e.g., PEG) are described by Sears (U.S. Patent Nos. 4,426,330 and 4,534,899). Klibanov et al. {FEBS Letts., 1990, 268, 235) described experiments demonstrating that liposomes comprising phosphatidylethanolamine (PE) derivatized with PEG or PEG stearate have significant increases in blood circulation half- lives. Blume et al. {Biochimica et Biophysica Acta, 1990, 1029, 91) extended such observations to other PEG-derivatized - 50 - phospholipids, e.g., DSPE-PEG, formed from the combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalently bound PEG moieties on their external surface are described in European Patent No. 0,445,131 Bl and WO 90/04384 to Fisher. Liposome compositions containing 1-20 mole percent of PE derivatized with PEG, and methods of use thereof, are described by Woodle et al . (U.S. Patent Nos. 5,013,556 and 5,356,633) and Martin et al . (U.S. Patent No. 5,213,804 and European Patent No. EP 0,496,813 Bl). Liposomes comprising a number of other lipid-polymer conjugates are disclosed in WO 91/05545 and U.S. Patent No. 5,225,212 (both to Martin et al . ) and in WO 94/20073 (Zalipsky et al . ) Liposomes comprising PEG-modified ceramide lipids are described in WO 96/10391 (Choi et al . ) . U.S. Patent Nos. 5,540,935 (Miyazaki et al . ) and 5,556,948 (Tagawa et al . ) describe PEG-containing liposomes that can be further derivatized via functional surface moieties. A limited number of liposomes comprising nucleic acids are known in the art. Published PCT application No. WO 96/40062 to Thierry et al . discloses methods for encapsulating high molecular weight nucleic acids in liposomes. U.S. Patent No. 5,264,221 to Tagawa et al . discloses protein-bonded liposomes and asserts that the contents of such liposomes may include an antisense RNA. U.S. Patent No. 5,665,710 to Rahman et al . describes certain methods of encapsulating oligodeoxynucleotides in liposomes. WO 97/04787 to Love et al . discloses liposomes comprising antisense oligonucleotides targeted to the raf gene. WO 97/46671 to Klimuk et al . discloses liposomes comprising antisense oligonucleotides targeted to genes encoding ICAM-1. One or more antisense compounds of the invention can be formulated in a [lipid: (antisense compound)] complex comprising one or more cationic lipids as disclosed in U.S. Patent No. 5,705,385 to - 51 - Bally et al . and in WO 96/40964 to Wheeler et al . , or in lipoprotein-containing complexes such as are described in WO 98/00556 to Kim et al . The liposomes of the invention can be prepared by any of a variety of known techniques. For example, the liposomes can be formed by any conventional technique for preparing multilamellar lipid vesicles (MLVs), i.e., by depositing one or more selected lipids on the inside wall of a suitable vessel by dissolving the lipid in chloroform, evaporating the chloroform and then adding an aqueous solution which comprises the agent (s) to be encapsulated to the vessel, allowing the aqueous solution to hydrate the lipid, and swirling or vortexing the resulting lipid suspension. This process yields a mixture including the desired liposomes. As another example, techniques used for producing large unilamellar vesicles (LUVs), such as, e.g., reverse-phase evaporation, infusion procedures and detergent dilution, can be used to produce the liposomes. These and other methods for producing lipid vesicles are described in Liposome Technology, Volume I (Gregoriadis, Ed., CRC Press, Boca Raton, FL, 1984). The liposomes can be in the form of steroidal lipid vesicles, stable plurilamellar vesicles (SPLVs), monophasic vesicles (MPVs) or lipid matrix carriers (LMCs) of the type disclosed in U.S. Patents Nos. 4,588,578 and 4,610,868 (both to Fountain et al . ) , 4,522,803 (to Lenk et al . ) , and 5,008,050 (to Cullis et al . ) . In the case of MLVs, the liposomes can be subjected to multiple (five or more) freeze-thaw cycles to enhance their trapped volumes and trapping efficiencies and to provide a more uniform interlamellar distribution of solute if desired (Mayer et al . , J. Biol . Chem . , 1985, 260, 802). Specific methods for making particular oligodeoxynucleotide : liposome compositions are described in U.S. Patent 5,665,710 to Rahman et al . - 52 - Following their preparation, liposomes may be sized to achieve a desired size range and relatively narrow distribution of sized particles. In preferred embodiments, the liposomes have a lower range of diameters of from about 50 to about 75 nM, most preferably about 60 nM, and an upper range of diameters from about 75 to about 150 nM, most preferably about 125 nM, where "about" indicates ± 10 nM. Several techniques are available for sizing liposomes to a desired size range. Sonicating a liposome suspension by either bath or probe sonication produces a progressive size reduction down to small unilamellar vesicles (SUVs) less than about 0.05 microns in size. Homogenization, which relies on shearing energy to fragment large liposomes into smaller ones, is another known sizing technique in which MLVs are recirculated through a standard emulsion homogenizer until a selected liposome size range, typically between about 0.1 and about 0.5 microns, is achieved. Extrusion of liposomes through a filter or membrane is another method for producing liposomes having a desired size range (see, for example, U.S. Patents 4,737,323 to Martin et al . and 5,008,050 to Cullis et al . ) . Other useful sizing methods are known to those skilled in the art. In most such methods, the particle size distribution can be monitored by conventional laser-beam size determination or other means known in the art. Liposomes may be dehydrated, preferably under reduced pressure using standard freeze-drying equipment, for extended storage. Whether dehydrated or not, the liposomes and their surrounding media can first be frozen in liquid nitrogen and placed under reduced pressure. Although the addition of the latter freezing step makes for a longer overall dehydration process, there is less damage to the lipid vesicles, and less loss of their internal contents, when the liposomes are frozen before dehydration. - 53 - To ensure that the a significant portion of the liposomes will endure the dehydration process intact, one or more protective sugars may be made available to interact with the lipid vesicle membranes and keep them intact as water is removed. Appropriate sugars include, but are not limited to, trehalose, maltose, sucrose, lactose, glucose, dextran and the like. In general, disaccharide sugars may work better than monosaccharide sugars, with trehalose and sucrose being particularly effective in most cases, but other, more complicated sugars may alternatively be used. The amount of sugar to be used depends on the type of sugar and the characteristics of the lipid vesicles. Persons skilled in the art can readily test various sugars and concentrations to determine what conditions work best for a particular lipid vesicle preparation (see, generally, Harrigan et al . , Chem . Phys . Lipids, 1990, 52, 139, and U.S. Patent No. 4,880,635 to Janoff et al . ) . Generally, sugar concentrations of greater than or equal to about 100 mM have been found to result in the desired degree of protection. Once the liposomes have been dehydrated, they can be stored for extended periods of time until they are to be used. The appropriate conditions for storage will depend on the chemical composition of the lipid vesicles and their encapsulated active agent (s). For example, liposomes comprising heat labile agents should be stored under refrigerated conditions so that the potency of the active agent is not lost. Two or more bioactive agents (e.g., an oligonucleotide and a conventional drug, or two or more oligonucleotides; see below) can be combined within, and delivered by, a single liposome. It is also possible to add agenrs to colloidal dispersion systems which enhance the intercellular stability and/or targeting of the contents thereof. - 54 - 5. Methods of Administration of Compounds of the Invention: The administration of therapeutic or pharmaceutical compositions comprising the antisense compounds of the invention is believed to be within the skill of those in the art. In general, a patient in need of therapy or prophylaxis is administered a composition comprising one or more antisense compounds in accordance with the invention, commonly in a pharmaceutically acceptable carrier, in doses ranging from 0.01 ug to 100 g per kg of body weight depending on the age of the patient and the severity of the disorder or disease state being treated. Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution or prevention of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual antisense compounds, and can generally be estimated based on EC 50 s found to be effective in in vi tro and in vivo animal models. A. Treatment Regimens: In the context of the invention, the term "treatment regimen" is meant to encompass therapeutic, palliative and prophylactic modalities of administration of one or more compositions comprising one or more antisense compounds of the invention. A particular treatment regimen may last for a period of time which will vary depending upon the nature of the particular disease or disorder, its severity and the overall condition of the patient, and may extend from once daily to once every 20 years. Following treatment, the patient is monitored for changes in his/her condition and for alleviation of the - 55 - symptoms of the disorder or disease state. The dosage of the oligonucleotide may either be increased in the event the patient does not respond significantly to current dosage levels, or the dose may be decreased if an alleviation of the symptoms of the disorder or disease state is observed, or if the disorder or disease state has been ablated. An optimal dosing schedule is used to deliver a therapeutically effective amount of the oligonucleotide being administered via a particular mode of administration. The term "therapeutically effective amount," for the purposes of the invention, refers to the amount of oligonucleotide- containing pharmaceutical composition which is effective to achieve an intended purpose without undesirable side effects (such as toxicity, irritation or allergic response) . Although individual needs may vary, determination of optimal ranges for effective amounts of pharmaceutical compositions is within the skill of the art. Human doses can be extrapolated from animal studies (Katocs et al . , Chapter 27 In : Remington ' s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990). Generally, the dosage required to provide an effective amount of a pharmaceutical composition, which can be adjusted by one skilled in the art, will vary depending on the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy (if any) and the nature and scope of the desired effect (s) (Nies et al . , Chapter 3 In : Goodman & Gilman ' s The Pharma cological Basis of Therapeutics, 9th Ed., Hardman et al . , eds., McGraw-Hill, New York, NY, 1996). Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the nucleic acid is administered in maintenance doses, ranging from 0.01 ug to 100 - 56 - g per kg of body weight, once or more daily, to once every 20 years. For example, in the case of in individual known or suspected of being prone to an autoimmune or inflammatory condition, prophylactic effects may be achieved by administration of preventative doses, ranging from 0.01 ug to 100 g per kg of body weight, once or more daily, to once every 20 years. In like fashion, an individual may be made less susceptible to an inflammatory condition that is expected to occur as a result of some medical treatment, e.g., graft versus host disease resulting from the transplantation of cells, tissue or an organ into the individual. In another method of the invention, a first antisense oligonucleotide targeted to a first PECAM-1 protein is used in combination with a second antisense oligonucleotide targeted to a second PECAM-1 protein in order to modulate such PECAM-1 proteins to a more extensive degree than can be achieved when either oligonucleotide is used individually. In various embodiments of the invention, the first and second PECAM-1 proteins which are targeted by such oligonucleotides are identical, are different PECAM-1 proteins or are different isoforms of the same PECAM-1 protein. In some cases it may be more effective to treat a patient with a composition comprising one or more antisense compounds of the invention in conjunction with other, traditional therapeutic modalities in order to increase the efficacy of a treatment regimen. In the context of the invention, the term "treatment regimen" is meant to encompass therapeutic, palliative and prophylactic modalities. Following treatment, the patient is monitored for changes in his/her condition and for alleviation of the symptoms of the disorder or disease state. The dosage of the therapeutic or pharmaceutical composition may either be increased in the event the patient does not respond significantly to current dosage levels, or - 57 - the dose may be decreased if an alleviation of the symptoms of the disorder or disease state is observed, or if the disorder or disease state has been ablated. Prophylactic modalities for high risk individuals are also encompassed by the invention. As used herein, the term "high risk individual" is meant to refer to an individual for whom it has been determined, via, e.g., individual or family history or genetic testing, that there is a significantly higher than normal probability of being susceptible to the onset or recurrence of a disease or disorder. As part of a treatment regimen for a high risk individual, the individual can be prophylactically treated to prevent the onset or recurrence of the disease or disorder. The term "prophylactically effective amount" is meant to refer to an amount of a pharmaceutical composition which produces an effect observed as the prevention of the onset or recurrence of a disease or disorder. Prophylactically effective amounts of a pharmaceutical composition are typically determined by the effect they have compared to the effect observed when a second pharmaceutical composition lacking the active agent is administered to a similarly situated individual. The therapeutic and pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Typically, either oral or parenteral administration is employed. B. Parenteral Delivery: The term "parenteral delivery" refers to the administration of one or more antisense compounds of the invention to an animal in a manner other than through the digestive canal. Parenteral administration includes intravenous (i.v.) drip, subcutaneous, intraperitoneal (i.p.) or intramuscular injection, or intrathecal or intraventricular administration. Compositions - 58 - for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. Means of preparing and administering parenteral pharmaceutical compositions are known in the art (see, e.g., Avis, Chapter 84 In : Remington ' s Pharma ceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, pages 1545-1569). Parenteral means of delivery include, but are not limited to, the following illustrative examples. Intravitreal injection, for the direct delivery of drug to the vitreous humor of a mammalian eye, is described m U.S. Patent No. 5,591,720, the contents of which are hereby incorporated by reference. Means of preparing and administering ophthalmic preparations are known m the art (see, e.g., Mullins et al . , Chapter 86 In : Remington ' s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, pages 1581-1595). Intravenous administration of antisense oligonucleotides to various non-human mammals has been described by Iversen (Chapter 26 In : Antisense Research and Applica tions, Crooke et al . , eds., CRC Press, Boca Raton, FL, 1993, pages 461-469). Systemic delivery of oligonucleotides to non-human mammals via intraperitoneal means has also been described (Dean et al . , Proc . Na tl . Acad . Sci . U. S . A . , 1994, 91 , 11766) . Intraluminal drug administration, for the direct delivery of drug to an isolated portion of a tubular organ or tissue (e.g., such as an artery, vein, ureter or urethra), may be desired for the treatment of patients with diseases or conditions afflicting the lumen of such organs or tissues. To effect this mode of oligonucleotide administration, a catheter or cannula is surgically introduced by appropriate means. For example, for treatment of the left common carotid - 59 - artery, a cannula is inserted thereinto via the external carotid artery. After isolation of a portion of the tubular organ or tissue for which treatment is sought, a composition comprising the antisense compounds of the invention is infused through the cannula or catheter into the isolated segment. After incubation for from about 1 to about 120 minutes, during which the oligonucleotide is taken up by cells of the interior lumen of the vessel, the infusion cannula or catheter is removed and flow within the tubular organ or tissue is restored by removal of the ligatures which effected the isolation of a segment thereof (Morishita et al . , Proc . Na tl . Acad . Sci . U. S . A . , 1993, 90, 8474). Antisense oligonucleotides may also be combined with a biocompatible matrix, such as a hydrogel material, and applied directly to vascular tissue in vivo (Rosenberg et al . , U.S. Patent No. 5,593,974, issued January 14, 1997). Intraventricular drug administration, for the direct delivery of drug to the brain of a patient, may be desired for the treatment of patients with diseases or conditions afflicting the brain. To effect this mode of oligonucleotide administration, a silicon catheter is surgically introduced into a ventricle of the brain of a human patient, and is connected to a subcutaneous infusion pump (Medtronic Inc., Minneapolis, MN) that has been surgically implanted in the abdominal region (Zimm et al . , Cancer Research, 1984, 44, 1698; Shaw, Cancer, 1993, 72 (11 Suppl . , 3416). The pump is used to inject the oligonucleotides and allows precise dosage adjustments and variation in dosage schedules with the aid of an external programming device. The reservoir capacity of the pump is 18-20 mL and infusion rates may range from 0.1 mL/h to 1 mL/h. Depending on the frequency of administration, ranging from daily to monthly, and the dose of drug to be administered, ranging from 0.01 ug to 100 g per kg of body - 60 - weight, the pump reservoir may be refilled at 3-10 week intervals. Refilling of the pump is accomplished by percutaneous puncture of the pump's self-seaJ ing septum. Intrathecal drug administration, for the introduction of a drug into the spinal column of a patient may be desired for the treatment of patients with diseases of the central nervous system (CNS) . To effect this route of oligonucleotide administration, a silicon catheter is surgically implanted into the L3-4 lumbar spinal interspace of a human patient, and is connected to a subcutaneous infusion pump which has been surgically implanted in the upper abdominal region (Luer and Hatton, The Annals of Pharmacotherapy, 1993, 27, 912, 1993; Ettinger et al . Cancer, 1978, 41 , 1270; Yaida et al . , Regul . Pept . , 1985, 59, 193). The pump is used to inject the oligonucleotides and allows precise dosage adjustments and variations in dose schedules with the aid of an external programming device. The reservoir capacity of the pump is 18-20 mL, and infusion rates may vary from 0.1 mL/h to 1 mL/h. Depending on the frequency of drug administration, ranging from daily to monthly, and dosage of drug to be administered, ranging from 0.01 ug to 100 g per kg of body weight, the pump reservoir may be refilled at 3-10 week intervals. Refilling of the pump is accomplished by a single percutaneous puncture to the self-sealing septum of the pump. The distribution, stability and pharmacokinetics of oligonucleotides within the CNS are followed according to known methods (Whitesell et al . , Proc . Na tl . Acad. Sci . U. S . A. , 1993, 90, 4665) . To effect delivery of oligonucleotides to areas other than the brain or spinal column via this method, the silicon catheter is configured to connect the subcutaneous infusion pump to, e . g. , the hepatic artery, for delivery to the liver (Kemeny et al . , Cancer, 1993, 71 , 1964) . Infusion pumps may - 61 - also be used to effect systemic delivery of oligonucleotides (Ewel et al . , Cancer Res . , 1992, 52, 3005; Rubenstein et al . , J. Surg. Oncol . , 1996, 62, 194). Epidermal and Transdermal Delivery, in which pharmaceutical compositions containing drugs are applied topically, can be used to administer drugs to be absorbed by the local dermis or for further penetration and absorption by underlying tissues, respectively. Means of preparing and administering medications topically are known in the art (see, e . g. , Block, Chapter 87 In : Remington ' s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, pages 1596-1609) . Vaginal Delivery provides local treatment and avoids first pass metabolism, degradation by digestive enzymes, and potential systemic side-effects. This mode of administration may be preferred for antisense oligonucleotides targeted to pathogenic organisms for which the vagina is the usual habitat, e.g., Trichomonas vaginalis . In another embodiment, antisense oligonucleotides to genes encoding sperm-specific antibodies can be delivered by this mode of administration in order to increase the probability of conception and subsequent pregnancy. Vaginal suppositories (Block, Chapter 87 In : Remington ' s Pharmaceu tical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, pages 1609-1614) or topical ointments can be used to effect this mode of delivery. Intravesical Delivery provides local treatment and avoids first pass metabolism, degradation by digestive enzymes, and potential systemic side-effects. However, the method requires urethral catheterization of the patient and a skilled staff. Nevertheless, this mode of administration may be preferred for antisense oligonucleotides targeted to pathogenic organisms, such as T. vaginalis, which may invade the urogenital tract. - 62 - C. Alimentary Delivery: The term "alimentary delivery" refers to the administration, directly or otherwise, to a portion of the alimentary canal of an animal, of a composition comprising one or more of the antisense compounds of the invention. The term "alimentary canal" refers to the tubular passage in an animal that functions in the digestion and absorption of food and the elimination of food residue, which runs from the mouth to the anus, and any and all of its portions or segments, e.g., the oral cavity, the esophagus, the stomach, the small and large intestines and the colon, as well as compound portions thereof such as, e.g., the gastrointestinal tract. Thus, the term "alimentary delivery" encompasses several routes of administration including, but not limited to, oral, rectal, endoscopic and sublingual/buccal administration. Compositions for alimentary delivery may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. Means of preparing and administering oral pharmaceutical compositions are known in the art (see, e.g., Block, Chapter 87; Rudnic, Chapter 89; Porter, Chapter 90; and Longer, Chapter 91, In : Remington ' s Pharma ceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, pages 1596-1614, 1633- 1665, 1666-1675 and 1676-1693, respectively) . Preferred compositions for the alimentary delivery of the antisense compounds of the invention are described in co-pending U.S. patent application Serial No. 08/886,829 to Teng et al . , filed July 1, 1997, the entire disclosure of which is hereby incorporated by reference. Buccal/Sublingual Aiministration: Delivery of a drug via the oral mucosa has several desirable features, including, in many instances, a more rapid rise in plasma concentration of the drug than via oral delivery (Harvey, Chapter 35 In : Remington ' s Pharmaceutical Sciences, 18th Ed., - 63 - Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, page 711) . Furthermore, because venous drainage from the mouth is to the superior vena cava, this route also bypasses rapid first-pass metabolism by the liver. Both features contribute to the sublingual route being the mode of choice for nitroglycerin (Benet et al . , Chapter 1 In : Goodman & Gilman ' s The Pharma cological Basis of Therapeutics, 9th Ed., Hardman et al . , eds., McGraw-Hill, New York, NY, 1996, page 7). Endoscopic Administration: Endoscopy can be used for drug delivery directly to an interior portion of the alimentary tract. For example, endoscopic retrograde cystopancreatography (ERCP) takes advantage of extended gastroscopy and permits selective access to the biliary tract and the pancreatic duct (Hirahata et al . , Gan To Kagaku Ryoho, 1992, 19 (10 Suppl . ) , 1591). Pharmaceutical compositions, including liposomal formulations, can be delivered directly into portions of the alimentary canal, such as, e.g., the duodenum (Somogyi et al . , Pharm . Res . , 1995, 12, 149) or the gastric submucosa (Akamo et al . , Japanese J. Cancer Res . , 1994, 85, 652) via endoscopic means. Gastric lavage devices (Inoue et al . , Art if . Organs, 1997, 21 , 28) and percutaneous endoscopic feeding devices (Pennington et al . , Aliment . Pharmacol . Ther . , 1995, 9, 471) can also be used for direct alimentary delivery of pharmaceutical compositions. Rectal Administration: Drugs administered by the oral route can often be alternatively administered by the lower enteral route, i . e . , through the anal portal into the rectum or lower intestine. Rectal suppositories, retention enemas or rectal catheters can be used for this purpose and may be preferred when patient compliance might otherwise be difficult to achieve (e.g., in pediatric and geriatric applications, or when the patient is vomiting or unconscious) . Rectal administration may result in more prompt and higher - 64 - blood levels than the oral route, but the converse may be true as well (Harvey, Chapter 35 In : Remington ' s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, page 711) . Because about 50% of the drug that is absorbed from the rectum will bypass the liver, administration by this route significantly reduces the potential for first- pass metabolism (Benet et al . , Chapter 1 In : Goodman & Gilman ' s The Pharma cological Basis of Therapeutics, 9th Ed., Hardman et al . , eds., McGraw-Hill, New York, NY, 1996). Oral Administration: The preferred method of administration is oral delivery, which is typically the most convenient route for access to the systemic circulation. Absorption from the alimentary canal is governed by factors that are generally applicable, e.g., surface area for absorption, blood flow to the site of absorption, the physical state of the drug and its concentration at the site of absorption (Benet et al . , Chapter 1 In : Goodman & Gilman ' s The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al . , eds., McGraw-Hill, New York, NY, 1996, pages 5-7). Orally administered compositions comprising certain oligonucleotides are known in the art (see, for example, U.S. Patent No. 5,591,721 to Agrawal et al . ) . Preferred compositions for the oral delivery of the antisense compounds of the invention are described in co-pending U.S. patent application Serial No. 08/886,829 to Teng et al . , filed July 1, 1997, incorporated herein by reference. EXAMPLES The following examples illustrate the invention and are not intended to limit the same. Those skilled in the art will recognize, or be able to ascertain through routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents - 65 - are considered to be within the scope of the present invention . Ex-ample 1 : Synthesis of Oligonucleotides A. General Synthetic Techniques: Oligonucleotides were synthesized on an automated DNA synthesizer using standard phosphoramidite chemistry with oxidation using iodine. β- Cyanoethyldiisopropyl phosphoramidites were purchased from Applied Biosystems (Foster City, CA) . For phosphorothioate oligonucleotides, the standard oxidation bottle was replaced by a 0.2 M solution of 3H-1, 2-benzodithiole-3-one-l, 1-dioxide in acetonitrile for the stepwise thiation of the phosphite linkages . The synthesis of 2 ' -O-methyl- (a.k.a. 2'-methoxy-) phosphorothioate oligonucleotides is according to the procedures set forth above substituting 2 ' -O-methyl β- cyanoethyldiisopropyl phosphoramidites (Chemgenes, Needham, MA) for standard phosphoramidites and increasing the wait cycle after the pulse delivery of tetrazole and base to 360 seconds . Similarly, 2'-0-propyl- (a.k.a 2'-propoxy-) phosphorothioate oligonucleotides are prepared by slight modifications of this procedure and essentially according to procedures disclosed in U.S. patent application Serial No. 08/383,666, filed February 3, 1995, which is assigned to the same assignee as the instant application. The 2 ' -fluoro-phosphorothioate antisense compounds of the invention are synthesized using 5 ' -dimethoxytrityl-3 ' - phosphoramidites and prepared as disclosed in U.S. patent application Serial No. 08/383,666, filed February 3, 1995, and U.S. Patent 5,459,255, which issued October 8, 1996, both of which are assigned to the same assignee as the instant application. The 2 ' -fluoro-oligonucleotides were prepared - 66 - using phosphoramidite chemistry and a slight modification of the standard DNA synthesis protocol (i.e., deprotection was effected using methanolic ammonia at room temperature) . The 2 ' -methoxyethyl oligonucleotides were synthesized essentially according to the methods of Martin et al . ( Helv. Chim . Acta , 1995, 78, 486). For ease of synthesis, the 3' nucleotide of the 2 ' -methoxyethyl oligonucleotides was a deoxynucleotide, and 2 ' -0-CH 2 CH 2 OCH 3 _cytosines were 5-methyl cytosines, which were synthesized according to the procedures described below. PNA antisense analogs are prepared essentially as described in U.S. Patents Nos. 5,539,082 and 5,539,083, both of which (1) issued July 23, 1996, and (2) are assigned to the same assignee as the instant application. B. 5-Methyl-2 ' -Methoxyethoxy-Cytosine: Oligonucleotides having 5-methyl-2 ' -methoxyethoxy-cytosine residues are prepared as follows. (i) 2,2' -Anhydro [1- (β-D-arabinofuranosyl) -5- methyluridine] : 5-Methyluridine (ribosylthymine, commercially available through Yamasa, Choshi, Japan) (72.0 g, 0.279 M) , diphenylcarbonate (90.0 g, 0.420 M) and sodium bicarbonate (2.0 g, 0.024 M) were added to DMF (300 mL) . The mixture was heated to reflux, with stirring, allowing the evolved carbon dioxide gas to be released in a controlled manner. After 1 hour, the slightly darkened solution was concentrated under reduced pressure. The resulting syrup was poured into diethylether (2.5 L) , with stirring. The product formed a gum. The ether was decanted and the residue was dissolved in a minimum amount of methanol (ca. 400 mL) . The solution was poured into fresh ether (2.5 L) to yield a stiff gum. The ether was decanted and the gum was dried in a vacuum oven (60°C at 1 mm Hg for 24 h) to give a solid which was crushed - 67 - to a light tan powder (57 g, 85% crude yield) . The material was used as is for further reactions. (ii) 2 ' -O-Methoxyethyl-5-methylurιdine: 2,2'- Anhydro-5-methylurιdme (195 g, 0.81 M) , tris (2- methoxyethyl ) borate (231 g, 0.98 M) and 2-methoxyethanol (1.2 L) were added to a 2 L stainless steel pressure vessel and placed m a pre-heated oil bath at 160°C. After heating for 48 hours at 155-160°C, the vessel was opened and the solution evaporated to dryness and triturated with MeOH (200 mL) . The residue was suspended m hot acetone (1 L) . The insoluble salts were filtered, washed with acetone (150 L) and the filtrate evaporated. The residue (280 g) was dissolved in CH 3 CN (600 mL) and evaporated. A silica gel column (3 kg) was packed in CH,Cl,/acetone/MeOH (20:5:3) containing 0.5% Et 3 NH. The residue was dissolved in CH 2 C1 2 (250 mL) and adsorbed onto silica (150 g) prior to loading onto the column. The product was eluted with the packing solvent to give 160 g (63%) of product . (iii) 2 ' -O-Methoxyethyl-5 ' -O-dιmethoxytrityl-5- methyluridine: 2 ' -O-Methoxyethyl-5-methylurιdme (160 g, 0.506 M) was co-evaporated with pyridine (250 mL) and the dried residue dissolved in pyridine (1.3 L) . A first aliquot of dimethoxytrityl chloride (94.3 g, 0.278 M) was added and the mixture stirred at room temperature for one hour. A second aliquot of dimethoxytrityl chloride (94.3 g, 0.278 M) was added and the reaction stirred for an additional one hour. Methanol (170 L) was then added to stop the reaction. HPLC showed the presence of approximately 70% product. The solvent was evaporated and triturated with CH 3 CN (200 mL) . The residue was dissolved m CHCl (1.5 L) and extracted with 2x 500 mL of saturated NaHCO, and 2x 500 mL of saturated NaCl. The organic phase was dried over Na-,S0 4 , filtered and evaporated. 275 g of residue was obtained. The residue was - 68 - purified on a 3.5 kg silica gel column, packed and eluted with EtOAc/Hexane/Acetone (5:5:1) containing 0.5% Et 3 NH. The pure fractions were evaporated to give 164 g of product. Approximately 20 g additional was obtained from the impure fractions to give a total yield of 183 g (57%) . (iv) 3 ' -O-Acetyl-2 ' -O-me thoxye thy1 - 5 ' -O- dimethoxytrityl-5-methyluridine : 2 ' -O-Methoxyethyl-5 ' -0- dιmethoxytrιtyl-5-methylurιdιne (106 g, 0.167 M) , DMF/pyridme (750 mL of a 3:1 mixture prepared from 562 mL of DMF and 188 mL of pyridine) and acetic anhydride (24.38 mL, 0.258 M) were combined and stirred at room temperature for 24 hours. The reaction was monitored by tic by first quenching the tic sample with the addition of MeOH . Upon completion of the reaction, as judged by tic, MeOH (50 mL) was added and the mixture evaporated at 35°C. The residue was dissolved in CHC1 3 (800 mL) and extracted with 2x 200 mL of saturated sodium bicarbonate and 2x 200 mL of saturated NaCl. The water layers were back extracted with 200 mL of CHC1 3 . The combined organics were dried with sodium sulfate and evaporated to give 122 g of residue (approximately 90% product) . The residue was purified on a 3.5 kg silica gel column and eluted using EtOAc/Hexane (4:1) . Pure product fractions were evaporated to yield 96 g (84%) . (v) 3 ' -O-Acetyl-2 ' -O-me thoxye thy 1 - 5 ' -O- dimethoxytrityl-5-methyl-4-triazoleuridine : A first solution was prepared by dissolving 3 ' -O-acetyl-2 ' -O-methoxyethyl-5 ' -0- dιmethoxytπtyl-5-methylurιdme (96 g, 0.144 M) m CH N (700 mL) and set aside. Triethylamine (189 mL, 1.44 M) was added to a solution of triazole (90 g, 1.3 M) m CH 3 CN (1 L) , cooled to -5°C and stirred for 0.5 h using an overhead stirrer. P0C1 3 was added dropwise, over a 30 minute period, to the stirred solution maintained at 0-10°C, and the resulting mixture stirred for an additional 2 hours. The first solution - 69 - was added dropwise, over a 45 minute period, to the later solution. The resulting reaction mixture was stored overnight in a cold room. Salts were filtered from the reaction mixture and the solution was evaporated. The residue was dissolved m EtOAc (1 L) and the insoluble solids were removed by filtration. The filtrate was washed with Ix 300 mL of NaHC0 3 and 2x 300 mL of saturated NaCl, dried over sodium sulfate and evaporated. The residue was triturated with EtOAc to give the title compound. (vi) 2 ' -O-Methoxyethyl-5 ' -O-dimethoxytrityl-5- methylcytidine : A solution of 3 ' -O-acetyl-2 ' -O-methoxyethyl- 5 ' -0-dιmethoxytrιtyl-5-methyl-4-trιazoleuπdιne (103 g, 0.141 M) m dioxane (500 mL) and NH 4 OH (30 mL) was stirred at room temperature for 2 hours . The dioxane solution was evaporated and the residue azeotroped with MeOH (2x 200 mL) . The residue was dissolved in MeOH (300 mL) and transferred to a 2 liter stainless steel pressure vessel. Methanol (400 mL) saturated with NH 3 gas was added and the vessel heated to 100°C for 2 hours (thin layer chromatography, tic, showed complete conversion) . The vessel contents were evaporated to dryness and the residue was dissolved m EtOAc (500 mL) and washed once with saturated NaCl (200 mL) . The orgamcs were dried over sodium sulfate and the solvent was evaporated to give 85 g (95%) of the title compound. (vii) N 4 -Benzoyl-2 ' -O-methoxyethyl- 5 ' -O- dimethoxytrityl-5-methylcytidine: 2 ' -O-Methoxyethyl-5 ' -0- dιmethoxytrιtyl-5-methylcytιdιne (85 g, 0.134 M) was dissolved in DMF (800 mL) and benzoic anhydride (37.2 g, 0.165 M) was added with stirring. After stirring for 3 hours, tic showed the reaction to be approximately 95% complete. The solvent was evaporated and the residue azeotroped with MeOH (200 mL) . The residue was dissolved in CHCl ^ (700 mL) and extracted with saturated NaHCO (2x 300 mL) and saturated NaCl (2x 300 L) , - 70 - dried over MgSO„ and evaporated to give a residue (96 g) . The residue was chromatographed on a 1.5 kg silica column using EtOAc/Hexane (1:1) containing 0.5% Et 3 NH as the eluting solvent. The pure product fractions were evaporated to give 90 g (90%) of the title compound. (viii) N 4 -Benzoyl-2 ' -O-methoxyethyl-5 ' -O- dimethoxytrityl-5-methylcytidine-3 ' --amidite : N 4 -Benzoyl-2 ' -O- methoxyethyl-5 ' -O-dιmethoxytrιtyl-5-methylcytιdme (74 g, 0.10 M) was dissolved m CH->C1 ; (1 L) . Tetrazole dnsopropylamme (7.1 g) and 2-cyanoethoxy-tetra (isopropyl) phosphite (40.5 L, 0.123 M) were added with stirring, under a nitrogen atmosphere. The resulting mixture was stirred for 20 hours at room temperature (tic showed the reaction to be 95% complete) . The reaction mixture was extracted with saturated NaHC0 3 (lx 300 mL) and saturated NaCl (3x 300 mL) . The aqueous washes were back-extracted with CH 2 C1 2 (300 mL) , and the extracts were combined, dried over MgS0 4 and concentrated. The residue obtained was chromatographed on a 1.5 kg silica column using EtOAc\Hexane (3:1) as the elutmg solvent. The pure fractions were combined to give 90.6 g (87%) of the title compound. C. Purification: After cleavage from the controlled pore glass column (Applied Biosystems) and deblocking m concentrated ammonium hydroxide at 55°C for 18 hours, the oligonucleotides were purified by precipitation twice out of 0.5 M NaCl with 2.5 volumes ethanol. Analytical gel electrophoresis was accomplished m 20% acrylamide, 8 M urea, 45 mM Tπs-borate buffer, pH 7.0. Oligodeoxynucleotides and their phosphorothioate analogs were judged from electrophoresis to be greater than 80% full length material. 71 Example 2 : Nucleotide Se-quences of Oligonucleotides Targeted to PECAM-1 A. Oligonucleotides Targeted to Nucleic Acids Encoding Human PECAM-1: Table 1 lists the nucleotide sequences of a set of oligonucleotides designed to specifically hybridize to human PECAM-1 mRNAs and their corresponding ISIS and SEQ ID numbers. The nucleotide co-ordinates of the target gene and gene target regions are also included. The nucleotide coordinates are derived from GenBank Accession No. M28526, locus name "HUMPECAM1" (see also Newman et al . , Science , 1990, 247, 1219; SEQ ID NO: 1) . The abbreviations for gene target regions are as follows: 5'-UTR, 5' untranslated region; AUG, translation initiation region; ORF, open reading frame; stop, translation termination region; 3'-UTR, 3' untranslated region. The location of the target sequences complementary to those of the oligonucleotides is shown in Figure 1. The nucleotides of the oligonucleotides whose sequences are presented in Table 1 are connected by phosphorothioate linkages and are unmodified at the 2' position (i.e., 2'- deoxy) . After studies involving this initial set of oligonucleotides were conducted, a second group of oligonucleotides comprising additional chemical modifications was prepared. These "second generation" oligonucleotides, some of which are derived from the initial phosphorothioate oligonucleotides, are described in Table 2. 72 TABLE 1 Nucleotide Sequences of Phosphorothioate Oligonucleotides Targeted to Human PECAM-1 SEQ TARGET GENE GENE ISIS NUCLEOTIDE SEQUENCE ID NUCLEOTIDE TARGET NO (5' -> 3') NO CO-ORDINATES 1 REGION 8988 GCTCTGGTCACTTCTCCCGG 2 0006-0025 5'-UTR 8989 GAGAAACCCGCCCTGTGAAA 3 0036-0055 5'-UTR 8990 TCGGGCCATGACTCGCTCAG 4 0084-0103 5 ' -UTR 8991 CTGCATCCTGAGAGTGAAGA 5 0128-0147 AUG 8992 TGCACCGTCCAGTCCGGCAG 6 0265-0284 ORF 8993 CCATGTCTGTTGTGGGCCAC 7 0976-0995 ORF 8994 GTGCATCTGGCCTTGCTGTC 8 2358-2377 stop 8995 GGAGCAGGGCAGGTTCATAA 9 2449-2468 3' -UTR 8996 AACCGGCAGCTTAGCCTGAG 10 2487-2506 3 ' -UTR 11591 GAGCAGGGCAGGTTCATAAA 11 2448-2467 3 ' -UTR 11593 AGCTTAGCCTGAGGAATTGC 12 2480-2499 Ξ ' -UTR 11594 CCATCAAGGGAGCCTTCCGT 13 2332-2351 ORF 11595 CCAGGGATGTGCATCTGGCC 14 2367-2385 3' -UTR 11914 GACAGCAAGGCCAGATGCAC 15 sense control 8994 11915 TGCGTAGCTCGCGTCTGTCT 16 scrambled 8994 1 Co-ordinates from Genbank Accession No. M28526, locus name "HUMPECAM1", SEQ ID NO: 1. (N.B. : SEQ ID NOs: 17, IE = phosphodiester primers for PCR of human PECAM-1) 73 TABLE 2 Nucleotide Sequences of "Second Generation" Oligonucleotides Targeted to Human PECAM-1 ISIS NUCLEOTIDE SEQUENCE (5 ' -3 ' ) SQ T.ARGET NO ID REGION AND CH.EMICAL MODIFICATIONS 1 O 8994 GsTsGsCsAsTsCsTsGsGsCsCsTsTsGsCsTsGsTsC 8 stop 2358- 23 ~ '7 ISIS 899 -derived gapmers : 12466 GoToGoCoAoToCsTsGsGsCsCsTsTsGoCoToGoToC 8 stop 2358- 2 r " 12467 GsTsGsCsAsTsCsTsGsGsCsCsTsTsGsCsTsGsTsC 8 step 2358- 23 ~ 7 17555 GsTsGsCsAsTsCsTsGsGsCsCsTsTsGsCsTsGsTsC 8 step 2358- 23~7 17556 GsTsGsCsAsTsCsTsGsGsCsCsTsTsGsCsTsGsTsC 8 stop 2358- 23 ^ 7 1^557 GsTsGsCsAsTsCsTsGsGsCsCsTsTsGsCsTsGsTsC 8 stop 2358- 23^ 17559 GsTsGsCsAsTsCsTsGsGsCsCsTsTsGsCsTsGsTsC 8 stop 2358- 23 _ 7 17560 GsTsGsCsAsTsCsTsGsGsCsCsTsTsGsCsTsGsTsC 8 stop 2358- 23 ^ 7 ISIS 8994 and 8995 derived hemimers : 1^566 GsTsGsCsAsTsCsTsGsGsCsCsTsTsGsCsTsGsTsC 8 stop 2358- 23" , "7 17651 GsTsGsCsAsTsCsTsGsGsCsCsTsTsGsCsTsGsTsC 8 stop 2358- 23-,-, 17567 GsGsAsGsCsAsGsGsGsCsAsGsGsTsTsCsAsTsAsA 9 UTF 2449- 2468 74 Direct "Second-Generation" Compounds : 17561 TsCsCsTsTsCsCsAsGsGsGsAsTsGsTsGsCsAsTsC 19 3 ' UTR 237 1 - 2390 17562 TsGsAsAsAsTsAsCsAsGsGsGsAsTsTsAsTsCsTsG 20 3 ' UTR 24 11 - 24 30 17563 TsGsGsGsAsGsCsAsGsGsGsCsAsGsGsTsTsCsAsT 21 3 ' UTR 24 3 1 - 24 70 17564 TsGsGsCsCsTsTsGsCsTsGsTsCsTsAsAsGsTsTsC 22 s t op 2351 - 23 _ 0 17565 AsCsAsGsCsTsTsTsCsCsGsGsAsCsTsTsCsAsCsT 23 ORF 2291 - 23 C Q 17568 CsTsAsGsAsGsTsAsTsCsTsGsCsTsTsTsCsCsAsC 24 ORF 23 1 1 - 2330 17569 CsAsCsTsTsTsGsTsCsAsAsTsAsCsCsTsGsCsAsG 25 ORF 1301 - 1320 17570 AsCsTsCsTsCsTsGsTsGsCsTsCsTsTsCsAsTsGsG 26 ORF 04 01 - 04 20 14391 GsAsCsGsCsAsTsCsGsCsGsCsCsTsAsCsAsTsCsG 27 ICAM- s cram- bled control 17966 TsCsCsTsTsCsCsTsGsGsGsAsGsGsTsAsCsAsTsC 28 17561 3-base mismatch 17970 CsTsTsCsGsAsGsAsCsGsCsTsGsCsTsCsAsTsGsT 29 17561 scrambled control 1 Emboldened residues, 2 ' -methoxyethoxy-residues (others are 2'-deoxy-); underlined C ( "C" or "C" ) residues, 5-methyl-cytosines ; "o", phosphodiester linkage; "s", phosphorothioate linkage. 2 Base co-ordinates from Genbank Accession No. M28526, locus name "HUMPECAM1", SEQ ID NO: 1. SUBSTΠIΠΈ SHEET (RULE 26) 75 B . Oligonucleotides Targeted to Nucleic Acids Encoding Murine PECAM-1: Tables 3 and 4 describe the nucleotide sequences and chemistries of a set of oligonucleotides designed to specifically hybridize to murine PECAM-1-encoding mRNAs and their corresponding ISIS and SEQ ID numbers. The nucleotide co-ordinates of the target gene and gene target regions are also included. The nucleotide co-ordinates are derived from GenBank accession No. L06039, locus name "MUSPECAM1" (see also Figure 1 of Xie et al . , Proc . Na tl . Acad . Sci . U. S . A . , 1993, 90, 5569; SEQ ID NO: 30). T.ABLE 3 Nucleotide Sequences of Phosphorothioate Oligonucleotides Targeted to Murine PECAM-1 SEQ TARGET GENE GENE ISIS NUCLEOTIDE SEQUENCE ID NUCLEOTIDE TARGET NO (5' -> 3') NO CO-O.RDINATES x REGION 13983 GAAGCCTTCCGTTCTAGAGTAT 31 2246-2267 ORF 13984 CGCTGGTGCTCTATGCAAGCCT 32 0121-0142 ORF 13985 GTCTTCCGGCCATCCTCAGG 33 0005-0024 5' -UTR 13986 TGCAGACTGAAGCACTCAGC 34 0032-0051 5' -UTR 13987 CATCTTTGCTGCCGACTGAG 35 0082-0101 AUG 13988 GATGTCCACAAGGCACTCCA 36 0232-0251 ORF 13989 GGATACGCCATGCACCTTCA 37 0442-0461 ORF 13990 CAAAACGCTTGGGTGTCATT 38 1716-1735 ORF 13991 CCGCAATGAGCCCTTTCTTC 39 1862-1881 ORF - 76 13992 CCAATGACAACCACCGCAAT 40 1875-1894 ORF 13993 GTAATGGCTGTTGGCTTCCA 41 2035-2054 ORF 13994 GTCTCTGTGGCTCTCGTTCC 42 2178-2197 ORF 13995 TGCACTGCCTTGACTGTCTT 43 2281-2300 stop 13996 GAATCGGCTGCTCTTCTCGG 44 2325-2344 3' -UTR 13997 GGATTACTGCTTTCGGTGGG 45 2386-2405 3' -UTR 13998 CCCAACATGAACAAGGCAGC 46 2436-2455 3' -UTR 13999 CACAAGGAAGATAGGTCAGG 47 2491-2510 3' -UTR 14447 CCGACATCAGCGTTCTCTCT 48 13991 control scrambled 14448 AGCACGTCCTTGTTCGTTCT 49 13995 control scrambled 14449 GTAGAGCCTACGTACCTCCA 50 13989 control scram- 1 Co-ordinates from Genbank Accession No. L06039, locus name "MUSPECAMI", SEQ ID NO: 30. (N. B. : SEQ ID NOs: 51, 52 = phosphodiester primers for PCR of mouse PECAM-1 (ISIS 14244, 14245, respectively)) T.ABLE 4 Nucleotide Sequences of "Second Generation" Oligonucleotides Targeted to Murine PECAM-1 ISIS NUCLEOTIDE SEQUENCE (5'→3') SQ T^GET NO REGION AND CHEMICAL MODIFICATIONS 1 ID NO (BASES) 2 13989 GsGsAsTsAsCsGsCsCsAsTsGsCsAsCsCsTsTsCsA 37 ORF 0442- 0461 17049 GsGsAsTsAsCsGsCsCsAsTsGsCsAsCsCsTsTsCsA 37 ORF 0442- 0461 77 17050 GsGsAsTsAsCsGsCsCsAsTsGsCsAsCsCsTsTsCsA 37 ORF 0442- 0461 17051 GsGsAsTsAsCsGsCsCsAsTsGsCsAsCsCsTsTsCsA 37 ORF 0442- 0461 17052 GsGsAsTsAsCsGsCsCsAsTsGsCsAsCsCsTsTsCsA 37 ORF 0442- 0461 17053 GsGsAsTsAsCsGsCsCsAsTsGsCsAsCsCsTsTsCsA 37 ORF 0442- 0461 17054 GsGsAsTsAsCsGsCsCsAsTsGsCsAsCsCsTsTsCsA 37 ORF 0442- 0461 20380 GoGsAsTsAsCsGsCsCsAsTsGsCoAoCoCoToToCoA 37 ORF 0442- 0461 18539 GsAsGsCsAsTsCsGsCsGsAsTsAsCsCsTsCsTsAsC 53 13989 scrambled control 20381 GoAsGsCsAsTsCsGsCsGsAsTsAoCoCoToCoToAoC 53 13989 scrambled control 1 Emboldened residues, 2 ' -methoxyethoxy- residues (others are 2'-deoxy-) including "C" residues, 5-methyl-cytosmes; "o", phosphodiester linkage; "s", phosphorothioate linkage. Δ Base co-ordinates from Genbank Accession No. L06039, ^ ocus name "MUSPECAMI", SEQ ID NO: 30. Ex-ample 3 : Assays for Oligonucleotide-Mediated Inhibition of PECAM-1 mRNA Expression in HUVEC Cells A. General Techniques: In order to evaluate the activity of potential human PECAM-1-modulatmg oligonucleotides, human umbilical vein endothelial cells (HUVEC) from Clonetics Corporation (Walkersville, MD; alternatively, ATCC CRL-1730 from the .American Type Culture Collection, Rockville, MD, can be used) were grown and treated with oligonucleotides or control solutions as detailed below. For oligonucleotides targeting the murine PECAM-1 gene, oligonucleotide-treated cells were of the bEND.3 endothelial cell line (gift of Dr. - 78 - Werner Risau; see Montesano et al . , Cell , 1990, 62, 435, and Stepkowski et al . , J. Immunol . , 1994, 153, 5336). After harvesting, cellular extracts were prepared and examined for specific PECAM-1-encodmg mRNA levels or PECAM-1 protein levels (e.g., Northern or flow cytometry assays, respectively) . In all cases, "% expression" refers to the amount of PECAM-1-specιfic signal in an oligonucleotide- treated cell relative to an untreated cell (or a cell treated with a control solution that lacks oligonucleotide), and "% inhibition" is calculated as 100% - % Expression = % Inhibition. B. RNA Assays: The mRNA expression of each PECAM-1 protein was determined by using a nucleic acid probe specifically hybridizable thereto m "Northern" assays. Nucleic acid probes specific for human and murine PECAM-1 are described m Examples 4-6. The probes were radiolabelled by means well known in the art (see, e . g. , Short Protocols m Molecular Biology, 2nd Ed., Ausubel et al . , eds., John Wiley & Sons, New York, 1992, pages 3-11 to 2-3-44 and 4-17 to 4-18; Ruth, Chapter 6 m: Methods in Molecular Biology, Vol . 26 : Protocols for Oligonucleotide Conj uga tes, Agrawal, ed., Humana Press Inc., Totowa, NJ, 1994, pages 167-185; and Chapter 10 In : Molecular Cloning: A Labora tory Manual , 2nd Ed., Sambrook et al . , eds., pages 10.1-10.70). The blots were stripped and reprobed with a , P-labeled glyceraldehyde 3-phosphate dehydrogenase (G3PDH) probe (Clontech Laboratories, Inc., Palo Alto, CA) in order to confirm equal loading of RNA and to allow the levels of PECAM-1 transcripts to be normalized with regard to the G3PDH signals. - 79 - HUVEC (human) or bEND.3 (murine) cells were grown in, respectively, EGM (Clonetics, Walkersville, MD) or high- glucose DMEM (GIBCO-BRL L fe Technologies, Gaithersburg, MD) media containing 10% fetal bovine serum (FBS) in T-75 flasks until 80-90% confluent. At this time, the cells were washed 3x with 10 L of Opti-MEM media (GIBCO-BRL) . Then, 5 L of Opti-MEM media containing 10 (HUVEC) or 15 (bEND.3) ug/mL LIPOFECTIN ® (i.e., 1:1 (w/w) DOTMA/DOPE, where DOTMA = N-[l- (2 , 3-dιoleyoxy) propyl] -N, N, N-trimethylammonium chloride and DOPE = dioleoyl phosphatidylethanolamine; GIBCO-BRL) and an appropriate amount of oligonucleotide were added to the cells (the time of addition of oligonucleotide is t=0h in the experiments described herein) . As a control, cells were treated with LIPOFECTIN without oligonucleotide under the same conditions and for the same times as the oligonucleotide- treated samples. After 4 hours at 37°C (t=4h) , the medium was replaced with fresh EGM (HUVEC) or high glucose DMEM (bEND.3) media containing 10% FBS. The cells were typically allowed to recover for 2 hours. Total cellular RNA was then extracted m guanidmium, subjected to gel electrophoresis and transferred to a filter according to techniques known m the art (see, e.g., Chapter 7 In : Molecular Cl oning: A Labora tory Manual , 2nd Ed., Sambrook et al . , eds., pages 7.1-7.87, and Short Protocols m Molecular Biology, 2nd Ed., Ausubel et al . , eds., John Wiley & Sons, New York, 1992, pages 2-24 to 2-30 and 4-14 to 4-29) . Following RNA transfer, filters were typically hybridized overnight to a probe specific for the particular PECAM-1- encoding gene of interest in hybridization buffer (QUIKHYB™ hybridization solution, Stratagene, La Jolla, CA) . This was followed by two washes in 2x SSC, 0.1% SDS at room temperature (~24°C) for 15 minutes and one wash in 0. lx SSC, 0.1% SDS at 60°C for 30 minutes. Hybridizing bands were visualized by - 80 - exposure to X-OMAT AR film and quantitated using a PHOSPHORIMAGER ® essentially according to the manufacturer's instructions (Molecular Dynamics, Sunnyvale, CA) . Although quantitation via a PHOSPHORIMAGER or a comparable instrument is a preferred means of measuring RNA levels, the results of these "Northern" assays could be determined by other means known m the art. C. Protein Assays: HUVEC or bEND.3 cells were grown m 12 well plates and treated with oligonucleotides as described above, except that cells were generally allowed to recover overnight (e.g., generally about 18 hours) before protein extracts were prepared. Cells were washed and released by treatment with trypsm (GIBCO-BRL) or EDTA. Specifically, HUVEC cells were typically released by trypsm treatment, although EDTA treatment worked as well, whereas bEND.3 cells are preferentially released by treatment with 2 mM EDTA m Ca ++ - and Mg ++ -free lx PBS buffer (HBSS; GIBCO-BRL) . Cells were stained with an appropriate fluorescently labeled primary antibody that specifically recognizes the PECAM-1 protein under examination and the amount of each PECAM-1 protein was determined by using fluorescence-activated cell sorting (FACS ® ) techniques (see, e.g., U.S. patents Nos. 4,727,020 to Recktenwald, 5,223,398 to Kortright et al . , and 5,556,764 to Sizto et al . ) . The fluorescently labelled primary antibodies specific for each PECAM-1 protein are described in the appropriate Examples. Alternatively, unlabelled primary antibodies to PECAM-1 (some are described in the Examples) can be used and detected by the use of fluorescently-labelled secondary (i.e., specific for the primary antibody) antibodies. In alternative methods for measuring PECAM-1 levels, cell lysates and protein extracts are electrophoresed (SDS-PAGE), transferred to nitrocellulose filters and detected by means - 81 - known m the art (see, e.g., Chapter 18 In: Molecular Cloning: A Laboratory Manual, 2nd Ed., Sambrook et al., eds., pages 18.34, 18.47-18.54 and 18.60-18.75)). Unlabelled primary antibodies to PECAM-1 can be used and detected by means well known in the art including, for example, detection of the primary antibody by a secondary antibody that binds the primary antibody (see, e.g., Short Protocols m Molecular Biology, 2nd Ed., Ausubel et al., eds., John Wiley & Sons, New York, 1992, pages 10-33 to 10-35; and Chapter 18 In: Molecular Cloning: A Laboratory Manual, 2nd Ed., Sambrook et al., eds., pages 18.1-18.75 and 18.86-18.88) and quantitated using other antibody-based assays known in the art. Such antibody-based assays include, but are not limited to, ELISA assays, Western assays, and the like (see, for example, U.S. Patents Nos. 4,879,219 to Wands et al. and 4,837,167 to Schoemaker et al., and Short Protocols in Molecular Biology , 2nd Ed., Ausubel et al., eds., John Wiley & Sons, New York, 1992, pages 11-5 to 11-17) . PECAM-1 activity can be measured in appropriate cell adhesion assays known in the art (see, for example, Albelda et al., J. Cell Biol., 1991, 114, 1059; DeLisser et al., J. Biol. Chem., 1993, 268, 16307; and Muller et al., J. Exp. Med. , 1992, 175, 1401) . Example 4 : Antisense-Mediated Inhibition of Human PECAM-1 Expression by Phosphorothioate Oligonucleotides A. Human PECAM-1-Speci ic Probes: In initial screenings of a set of oligonucleotides derived from the human PECAM-1 sequence (Table 1) for biological activity, a radiolabelled PECAM-1-specιfic PCR product was prepared using RNA from HUVEC cells and a pair of phosphodiester oligonucleotides, 5 ' -TCCGATGTCAAGCTAGGATCAT (SEQ ID NO: 17); and 5 ' -GGCATGGGAATGGCAATTATCT (SEQ ID NO: 18), - 82 - as primers in PCR reactions using a PRIME-A-GENE ® labeling kit (Promega, Madison, WI) . The resultant 32 P-cytosme- radiolabelled 844-bp product hybridizes to the open reading frame of human PECAM-1 (nucleotides 752-1596 of Genbank Accession No. M28526, locus name "HUMPECAM1") . Alternatively, however, other PCR probes can be prepared, or one or more of the oligonucleotides of Tables 1 or 2 can be detectably labeled and used as a human PECAM-1-specιfic probe using methods known in the art. B. Activities of PECAM-1 Oligonucleotides: In an initial screen for active compounds capable of modulating PECAM-1 expression, HUVEC cells were treated with 100 nM of a series of PECAM-1-specιfic phosphorothioate oligonucleotides (ISIS 8988-8996, SEQ ID NOs: 2-10) and PECAM-1 mRNA levels were determined by Northern analysis. The data from the screening (Table 5, Experiment 1) indicate the following results. Oligonucleotides showing activity in this assay, as reflected by levels of inhibition from >. about 35% to about 100% of PECAM-1 mRNA levels, where "about" indicates ± 5%, include ISIS 8988, 8991, 8992, 8993, 8994, 8995 and 8996 (SEQ ID NOs: 2, 5, 6, 7, 8, 9 and 10, respectively) . These oligonucleotides are thus preferred embodiments of the invention for modulating PECAM-1 expression. Oligonucleotides showing levels of inhibition of from about 50% to about 100% of PECAM-1 mRNAs in this assay, where "about" indicates ± 5%, include ISIS 8994, 8995 and 8996 (SEQ ID NOs: 8, 9 and 10, respectively) . These oligonucleotides are thus more preferred embodiments of the invention for modulating PECAM-1 expression . Screening of a second set of phosphorothioate oligonucleotides (Table 5, Experiment 2) yielded additional antisense sequences against human PECAM-1. Specifically, oligonucleotides showing activity in this assay, as reflected - 83 - by levels of inhibition from >. about 50% to about 100% of PECAM-1 mRNA levels, where "about" indicates ± 5%, include ISIS 11591, 11593, 11594 and 11595 (SEQ ID NOs: 11, 12, 13 and 14, respectively); these oligonucleotides are thus preferred embodiments of the invention for modulating PECAM-1 expression. Oligonucleotides showing levels of inhibition of from > about 85% to about 100% of PECAM-1 mRNAs in this assay, where "about" indicates + 5%, include ISIS 11594 and 11595 (SEQ ID NOs: 13 and 14, respectively). These oligonucleotides are thus more preferred embodiments of the invention for modulating PECAM-1 expression. Among the phosphorothioate oligonucleotides initially screened, the most preferred embodiments of the invention are those showing levels of inhibition of from J> about 55% to about 100% of PECAM-1 mRNAs in this assay, where "about" indicates ± 5%, i.e., are ISIS 8994, 8996, 11591, 11593, 11594 and 11595 (SEQ ID NOs: 8, 10, 11, 12, 13 and 14, respectively) . C. Sequence Specificity: The specificity of modulation of PECAM-1 by the antisense oligonucleotides was confirmed using ISIS 8994 and a set of control oligonucleotides having sequences that are either sense (i.e., reverse complement) or scrambled versions of that of the active oligonucleotide. Specifically, ISIS 11914 (SEQ ID NO: 15) is a "sense" control, and ISIS 11915 (SEQ ID NO: 16) is a "scrambled" control, for ISIS 8994. HUVEC cells were treated with these oligonucleotides at 50 nM and evaluated by Northern analysis as above. The results (Table 6) demonstrate that, although the active oligonucleotide ISIS 8994 caused 90% inhibition of PECAM-1 mRNA under these conditions, treatment of cells with the control oligonucleotides had little effect on PECAM-1 mRNA expression (i.e., 14% inhibition for ISIS 11914 and 26% for - 84 - ISIS 11915) . Thus, the PECAM-1-modulating activity of the active antisense compounds is sequence-specific. D. Time Course: The time course of inhibition of PECAM-1 mRNA expression in HUVEC cells following treatment with 100 nM of ISIS 8994 or 8996 is shown in Table 7. After 4 hours of treatment with ISIS 8994, the level of inhibition of PECAM- 1 was greater than about 85% (t=4 h) , rose to about 98% inhibition at t=6 h, and subsequently remained at greater than or equal to about 95%, where "about" indicates ± 5%, until at least t=12 h. A similar pattern of temporal modulation of human PECAM-1 was seen for ISIS 8996. E. Protein Levels: In order to assess the correlation between PECAM-1 mRNA and protein levels, experiments were performed in which HUVEC cells were treated with 50 nM of various oligonucleotides and samples were taken at t=4h, 24h and 48h. The samples were split and (1) levels of PECAM-1 protein were determined by FACS using a monoclonal antibody to PECAM-1 (CD31) conjugated to phycoerythrin (PE) from Becton-Dickinson (Franklin Lakes, NJ) and (2) PECAM-1 mRNA levels were determined as in the previous Examples. FACS ® Θ results were similar whether cells were lysed with trypsin or EDTA and whether PE- or FITC- (fluorescein isothiocyanate) labelled antibodies to human PECAM-1 were used. PE- and FITC- labelled antibodies to human PECAM-1 are available from, for example, Becton-Dickinson (Franklin Lakes, NJ) ; Research Diagnostics, Inc. (RDI, Flanders, NJ) ; Boehringer Ingelheim Bioproducts (Heidelberg, Germany ) ; and BioSource (Camarillo, CA) . Isotypic (mouse IgG-1 kappa) controls typically gave signals of < 5% of the basal signal. Other primary antibodies to human PECAM-1 suitable for FACS ® analysis in combination with a labelled secondary antibody are available from, e.g., RDI; Boehringer Ingelheim Bioproducts; Endogen (formerly T Cell Diagnostics, Woburn, MA) ; PharMingen (San Diego, CA) ; OSI - 85 - Pharmaceuticals (formerly Oncogene Science, Uniondale, NY); Serotec (Oxford, England) ; and Santa Cruz Biotechnology (Santa Cruz, CA) . The results (Table 8) indicate that, at least for ISIS 8994 and 8995, inhibition of PECAM-1 mRNA expression occurs at a fairly constant level (from about 60 to 90% inhibition, where "about" indicates ± 5%) from t=4h to t=48h. In contrast, inhibition of PECAM-1 protein expression "lags behind" the antisense modulation of mRNA levels; that is, a reduction in PECAM-1 protein levels is not seen until the t=24h timepomt. Moreover, at least m the case of ISIS 8995, the antisense modulation of PECAM-1 protein expression may continue to increase beyond the last timepomt of the experiment (t=48 h) . F. Dose Response: The dose response of PECAM-1 protein expression m HUVEC cells following 24 hours of treatment with various concentrations of ISIS 8994 or 8996 is shown in Table 9. Levels of PECAM-1 protein were determined by FACS° as above. Under these conditions, both of these antisense oligonucleotides caused about 30% inhibition of PECAM-1 protein levels when applied at a concentration of 10 nM, where "about" indicates + 5%. For ISIS 8994, the degree of inhibition increased to about 50% at 25 nM and to about 60% at concentrations of 50 to 100 nM. For ISIS 8995, the degree of inhibition increased to about 50% at 25 nM and remained at that level at higher concentrations of the oligonucleotide. 86 T.ABLE 5 Activities of Phosphorothioate Antisense Oligonucleotides (ASOs) Targeted to Htiman PECAM-1 ISIS SEQ ID GENE T.ARGET % mRNA % mRNA No NO REGION EXPRESSION INHIBITION Expt. 1 (t=41i, [ASO] = 100 nM) basal LIPOFECTIN ® only 100% 0% 8988 2 5 ' -UTR 62% 38% 8989 3 5' -UTR 105% 8990 4 5' -UTR 91% 9% 8991 5 AUG 67% ' 33% 8992 6 ORF 60% 40% 8993 7 ORF 66% 34% 8994 8 stop 39% 61% 8995 9 3 ' -UTR 53% 47% 8996 10 3' -UTR 42% 58% Expt. 2 (t=6h, [ASO] = 100 nM: basal LIPOFECTIN ® only 100% 0% 11591 11 3' -UTR 50% 50% 11593 12 3' -UTR 44% 56% 11594 13 ORF 14% 86% 11595 14 3' -UTR 8% 92% 87 - TA. BLE 6 Sequence Specificity of Phosphorothioate Oligonucleotides Targeted to Human PECAM-1 ISIS SEQ GENE T.ARGET % mRNA % mRNA No ID REGION EXPRESSION X INHIBITION NO basal -- LIPOFECTIN ® 100% 0% only 8994 8 stop codon 10% 90% region 11914 15 sense control 86% 14% 11915 16 scrambled 74% 26% control 1 Oligonucleotide concentration = 50 nM, t = 4h. 88 - TABLE 7 Time Course of Response of HUVEC Cells to PECAM-1 Antisense Oligonucleotides (ASOs) SEQ ASO Gene % mRNA % mRNA ISIS # ID Target Region Time Expression InhiNO bition basal LIPOFECTIN ® only 4 h 100.0% 0.0% 8994 8 stop codon 4 h 14.4% 85.6% 8994 8 \\ 6 h 2.4% 97.6% 8994 8 8 h 3.5% 96.5% 8994 8 \\ 12 h 5.0% 95.0% 8996 10 3' -UTR 4 h 13.6% 86.4% 8996 10 \\ 6 h 2.5% 97.5% 8996 10 8 h 4.3% 95.7% 8996 10 w 12 h 6.2% 93.8% Oligonucleotide concentration = 100 nM. TABLE 8 Time Courses of Modulation of mRNA and Protein Levels by PECAM-1 Antisense Oligonucleotides (ASOs) SEQ ASO Gene % mRNA % Protein ISIS # ID Target Region Time ExpresExpresNO sion sion basal LIPOFECTIN ® only 4 h 100% 100% 8994 8 stop region 4 h 12% 97% 8995 9 3' -UTR 4 h 22% 92% basal LIPOFECTIN ® only 24 h 100% 100% 8994 8 stop region 24 h 39% 51% SUBSTrrUTE SHEET (RULE 26) - 89 8995 9 3' -UTR 24 h 30% 43% basal LIPOFECTIN ® only 48 h 100% 100% 8994 8 stop region 48 h 23% 55% 8995 9 3' -UTR 48 h 12% 28% 1 Oligonucleotide concentration = 50 nM. TABLE 9 Dose Response of HUVEC Cells to PECAM-1 Antisense Oligonucleotides (ASOs) SEQ ASO Gene ASO % Protein % Protein ISIS # ID Target Dose ExpresInhibiNO sion tion basal LIPOFECTIN ® only 0 nM 100% 0% 8994 8 stop codon 10 nM 62% 38% 8994 8 >\ 25 nM 48% 52% 8994 8 w 50 nM 41% 59% 8994 8 75 nM 40% 60% 8994 8 \\ 100 nM 40% 60% 8995 9 3' -UTR 10 nM 61% 39% 8995 9 \\ 25 nM 51% 49% 8995 9 \\ 50 nM 49% 51% 8995 9 \\ 75 nM 51% 49% 8995 9 \\ 100 nM 51% 49% t = 24 h. - 90 - Excunple 5 : Antisense-Mediated Inhibition of Human PECAM-1 Expression by Second Generation Oligonucleotides A. Design of "Second Generation" Human PECAM-1 oligonucleotides: Results from the PECAM-1-specιfic phosphorothioate oligonucleotides indicate that the most active phosphorothioate oligonucleotides for modulating PECAM- 1 expression include ISIS 8994 and 8995 (SEQ ID NOs: 8 and 9, respectively) . "Second generation" oligonucleotides based on these oligonucleotides but having additional chemical modifications were designed and synthesized to confirm and extend these findings. As detailed Table 2, ISIS 12466, 12467 and 17555 to 17560 are "gapmers" corresponding to ISIS 8994. That is, all of these oligonucleotides comprise SEQ ID NO: 8 and have 2 ' -methoxyethoxy flanks or "wmgs" and a central 2 ' -deoxy "gap" designed to support RNase H activity on the target mRNA molecule. ISIS 17566 and 17651 are hemimers (or "wmgmers") corresponding to ISIS 8994 and have a 2 ' -methoxyethoxy, RNase H-refractory 5' or 3 ' first portion and a 3' or 5', respectively, second portion (the "wing") that comprises 2 ' -deoxy residues. Like the central "gap" portion of the gapmers, the second, 2 ' -deoxy portion of the hemimer oligonucleotides is designed to support RNase H activity on the target PECAM-1 mRNA. The 2 ' -methoxyethoxy portions ("w gs") of these oligonucleotides also contain 5-methyl- cytid e (m5C) residues, which are known to increase duplex stability in some nucleic acids (see, for example, Hoheisel e t al . , J. Biol . Chem . , 1990, 265, 16656). Other "second generation" compounds have sequences that are not based on any of the phosphorothioate oligonucleotides of the previous example. These include ISIS 17561-17570 (SEQ ID NOs: 19-26, respectively) and two controls for ISIS 17561 (ISIS 17966 and 17970, SEQ ID NOs: 28 and 29, respectively) . - 91 - B. Activities of Second Generation PECAM-1 Oligonucleotides: The chemically modified derivatives of ISIS 8994 and 8995 (SEQ ID NOs: 8 and 9, respectively) were tested the PECAM-1 protein assay (FACS°) described above with the following modifications: oligonucleotides were added to cells to a final concentrations of 50 nM or 100 nM, and samples were taken for analysis at 24 h and/or 48 h, as indicated below. The results are presented m Table 10 (Experiments 1, 2a, 2b and 4) . (In Experiment 4, ISIS 14391 was used as a control; this oligonucleotide comprises the sequence 5'- GACGCATCGCGCCTACATCG (SEQ ID NO: 27), where emboldened residues indicate 2 ' -methoxyethoxy-modified residues and underlined "C" residues indicate 5-methylcytosme, and has a phosphorothioate backbone) . Because of their ability to modulate PECAM-1 expression for extended periods of time, as reflected by levels of inhibition from >. about 45% to 100% of PECAM-1 levels at t=24h, and from > about 30% to 100% at t=48h, where "about" indicates ± 5%, the chemically modified antisense oligonucleotides targeted to human PECAM-1 are preferred embodiments of the invention. Particularly preferred are ISIS 12467, 17555, 17556, 17557, 17559, 17560, 17561 and 17567. The additional oligonucleotides targeting human PECAM-1 were evaluated using the PECAM-1 protein assay. The results (Table 10, Experiment 3) indicate that all of the chemically modified oligonucleotides inhibit PECAM-1 protein levels from ≥ about 45% to about 100% of PECAM-1 levels at t=24h, where "about" indicates + 5%. Accordingly, such chemically modified antisense compounds are preferred embodiments of the invention. Particularly preferred are ISIS 17561, 17562, 17563, 17564, 17565, 17568, 17569 and 17570 (SEQ ID NOs: 19, 20, 21, 22, 23, 24, 25 and 26, respectively) . 92 The specificity of modulation of PECAM-1 oy the chemically modified antisense oligonucleotides was confirmed using ISIS 17561 and a set of control oligonucleotides navmg sequences that are either mismatched or scrambled versions of that of the active oligonucleotide. Specifically, ISIS 17966 (SEQ ID NO: 28) is a control oligonucleotide having 3 base mismatches with the target PECAM-1 sequence, and ISIS 17970 (SEQ ID NO: 29) is a "scrambled" control, for ISIS 17561. HUVEC cells were treated with these oligonucleotides at 25 nM and evaluated by FACS ® as above. The results (Table 10, Experiment 5) demonstrate that neither of the control oligonucleotides was capable of lnmbitmg PECAM-1 expression and thus are not within the range of activity of the preferred embodiments of the invention (i.e., inhibition of PECAM-1 protein levels from >. about 35% to about 100%) . In sum, the PECAM-1-modulatmg activities of the chemically modified ("second generation") antisense compounds are sequence- specific . T.ABLE 10 Activity of "Second Generation" Antisense Oligonucleotides Targeted to Human PECAM-1 ISIS SEQ ID ASO % % PROTEIN No NO DESCRIPTION PROTEIN INHIBITION EXPRESSION EXPT. 1 (50 nM, t=24 h) : basal LIPOFECTIN ® 100% 0% only 8994 8 active-stop 81% 19% codon 11915 16 scrambled 125% control-8994 - 93 12466 8 8994-derived 87% 13% gap er 12467 8 8994-derived 56% 44% gapmer EXPT. 2a (100 nM, t=24 h) : basal LIPOFECTIN ® 100% 0% only 8994 8 active-stop 55% 45% codon 11915 16 scrambled 93% 7% control-8994 17555 8 8994-derived 52% 48% gapmer 17556 8 8994-derived 42% 58% gapmer 17557 8 8994-derived 49% 51% gapmer 17559 8 8994-derived 55% 45% gapmer 17560 8 8994-derived 57% 43% gapmer 17651 8 8994-derived 51% 49% hemimer EXPT. 2b (100 nM, t=48 h) : basal LIPOFECTIN ® 100% 0% only 8994 8 active-stop 73% 27% codon 11915 16 scrambled 112% control-8994 17555 8 8994-derived 73% 27% gapmer 94 17556 8 8994-derived 64% 36% gapmer 17557 8 8994-derived 67% 34% gapmer 17559 8 8994-derived 73% 27% gapmer 17560 8 8994-derived 73% 27% gapmer 17651 8 8994-derived 70% 30% hemimer EXPT . 3 (100 nM, t=24 h) : basal LIPOFECTIN 0 100% 0% 17561 19 3' -UTR hemimer 30% 70% 17562 20 3' -UTR hemimer 35% 65% 17563 21 3' -UTR hemimer 44% 56% 17564 22 stop hemimer 37% 63% 17565 23 ORF hemimer 39% 61% 17566 8 8994-hemιmer 51% 49% 17567 9 8995-hemιmer 35% 65% 17568 24 ORF hemimer 37% 63% 17569 25 ORF hemimer 37% 63% 17570 26 ORF hemimer 36% 64% EXPT. 4 (100 nM, t=48h) : basal LIPOFECTIN ® 100% only 17561 19 3' -UTR 11% 89% hemimer 17567 9 8995-derived 48% 52% hemimer - 95 14391 27 scrambled 84% 16% ICAM-1 hemimer EXPT. 5 (25 nM, t = 48 h) : basal LIPOFECTIN ® 100% only 17561 19 3' -UTR 20% 80% hemimer 17966 28 17561 control 120% (mismatch) 17970 29 17561 control 99% 1% (scrambled) C . Preferred Regions for Antisense Modulation of Nucleic Acids Encoding Human PECAM-1: The antisense compounds of the invention may be designed to be specifically hybridizable (targeted) to any portion of a nucleic acid encoding PECAM-1. However, the above results indicate that several regions, and sequences within such regions, of nucleic acids encoding human PECAM-1 are particularly preferred for antisense modulation of, and are thus preferred target regions for further antisense compounds designed to modulate, human PECAM-1. 1. The 5' -UTR of human PECAM-1 was the target region for ISIS 8988 (SEQ ID NO: 2), a preferred embodiment of the invention. 2. The AUG (start) codon region of human PECAM-1 was the target region for ISIS 8991 (SEQ ID NO: 5), a preferred embodiment of the invention. 3. The O.RF (open reading frame) region of human PECAM-1 is the target region for ISIS 8992, 8993, 11594, 17565, 17569 and 17570 (SEQ ID NOs: 6, 7, 13, 23, 24, 25 and - 96 - 26, respectively) , all of which are preferred embodiments of the invention. 4. The stop codon region of human PECAM-1 is a target region for preferred embodiments of the invention. As shown in figure 2, the sequence of this region of human PECAM- 1 (bases 2305-2394 of SEQ ID NO: 1; GenBank Accession No. M28526) has a sequence (SEQ ID NO: 54) encompassing ISIS 17561, 11595, 8994, 17564, 11594 and 17568. Taken together, results from these oligonucleotides indicate that the stop codon region of nucleic acids that the human PECAM-1 is particularly susceptible to antisense modulation. More specifically, antisense compounds that specifically hybridize to SEQ ID NOs: 55 or 57 (see Figure 2) are preferred among those specifically hybridizing to the stop codon region of a nucleic acid encoding human PECAM-1. Particularly preferred are those antisense compounds comprising either of the consensus sequences derivable from the shared portions of 2 or more antisense compounds. For example, consensus sequences shared between two antisense compounds include SEQ ID NO: 58 (common to ISIS 17561 and 11595), SEQ ID NO: 59 (ISIS 11595 and 8994) and SEQ ID NO: 60 (ISIS 8994 and 17564). Especially preferred are antisense compounds comprising consensus sequences derivable from the shared portions of 3 or more antisense compounds, i.e., 5'- GTGCATC (common to ISIS 17561, 11595 and 8994) and 5 ' -TGGCC (common to ISIS 11595, 8994 and 17564). 5. The 3 '-UTR (untranslated region) of human PECAM-1 is a target region for preferred embodiments of the invention. As shown in figure 3, the sequence of this region of human PECAM-1 (bases 2436-2520 of SEQ ID NO: 1; GenBank Accession No. M28526) has a sequence (SEQ ID NO: 61) encompassing ISIS 8996, 11593, 17563, 8995 and 11591. Taken together, results from these oligonucleotides indicate that the 3 ' -untranslated - 97 - region (3' -UTR) of nucleic acids that the human PECAM-1 is particularly susceptible to antisense modulation. More specifically, antisense compounds that specifically hybridize to SEQ ID NOs: 62, 64 or 66 (see Figure 3) are preferred among those specifically hybridizing to the 3 ' -UTR of a nucleic acid encoding human PECAM-1. Particularly preferred are those antisense compounds comprising either of the consensus sequences derivable from the shared portions of 2 or more antisense compounds. For example, a consensus sequence shared between two antisense compounds is SEQ ID NO: 65 (common to ISIS 8996 and 11593) . Especially preferred are antisense compounds comprising consensus sequences derivable from the shared portions of 3 or more antisense compounds, i.e., SEQ ID NO: 67 (common to ISIS 17563, 8995 and 11591) . Example 6 : Antisense-Mediated Inhibition of Murine PECAM- 1 Expression by Phosphorothioate Oligonucleotides A. Murine PECAM-1-Specific Probes: In initial screenings of a set of oligonucleotides derived from the murine PECAM-1 sequence (Table 3) for biological activity, a radiolabelled mouse PECAM-1-specific PCR product was prepared using RNA from bEND.3 cells and a pair of phosphodiester oligonucleotides as PCR primers, i.e., 5 ' -GAGGACACTTCCACTTCTGTGT (ISIS 14244, SEQ ID NO: 51); and 5 ' -GGCCTGGTACCGATCCAGGTGT (ISIS 14245, SEQ ID NO: 52), in PCR reactions using a PRIME-A-GENE ® labeling kit (Promega, Madison, WI) . The resultant 32 P-cytidine-radiolabelled 898-bp product hybridizes to the open reading frame of murine PECAM-1 (nucleotides 1257-2155 of GenBank accession No. L06039, locus - 98 - name "MUSPECAM1") . Alternatively, however, other PCR probes can be prepared, or one or more of the oligonucleotides of Tables 3 or 4 can be detectably labeled and used as a murine PECAM-1-specific probe, using methods known in the art. B. Activities of Murine PECAM-1 Oligonucleotides: In an initial screen for active compounds capable of modulating PECAM-1 expression, bEND.3 cells were treated with 200 nM of a series of PECAM-1-specific phosphorothioate oligonucleotides (ISIS 13983-13999, SEQ ID NOs: 31-47) and PECAM-1 mRNA levels were determined by Northern analysis. The data from the screening (Table 11) indicate the following results. Oligonucleotides showing activity in this assay, as reflected by levels of inhibition from _> about 35% to about 100% of PECAM-1 mRNA levels, where "about" indicates ± 5%, include ISIS 13985, 13986, 13988, 13989, 13990, 13991, 13992, 13993, 13994, 13995 and 13996 (SEQ ID NOs: 33, 34, 36, 37, 38, 39, 40, 41, 42, 43 and 44, respectively) . These oligonucleotides are thus preferred embodiments of the invention for modulating murine PECAM-1 expression. Oligonucleotides showing levels of inhibition of from > about 50% to about 100% of PECAM-1 mRNAs in this assay, where "about" indicates ± 5%, include ISIS 13989, 13990, 13991, 13992, 13993, 13994, 13995 and 13996 (SEQ ID NOs: 37, 38, 39, 40, 41, 42, 43 and 44, respectively) . These oligonucleotides are thus more preferred embodiments of the invention for modulating murine PECAM-1 expression. Among the phosphorothioate oligonucleotides initially screened, the most preferred embodiments of the invention are those showing levels of inhibition of from >_ about 65% to about 100% of PECAM-1 mRNAs in this assay, where "about" indicates ± 5%, i.e., ISIS 13990, 13991, 13992 and 13995 (SEQ ID NOs: 38, 39, 40 and 43, respectively) . C. Sequence Specificity: The specificity of modulation of PECAM-1 by the antisense oligonucleotides was confirmed - 99 - using ISIS 13989 and a control oligonucleotide having a scrambled version of the sequence of the active oligonucleotide. Specifically, ISIS 14449 (SEQ ID NO: 50) is a "scrambled" control for ISIS 8994. BEND.3 cells were treated with these oligonucleotides at 50 nM and evaluated by FACS ® analysis at t=24h. In these experiments, murine PECAM-1 protein levels were measured by FACS° analysis using a monoclonal antibody to murine PECAM-1 conjugated to FITC (Pharmingen, San Diego, CA) . Isotypic (rat IgG-2a kappa) FITC-labelled controls typically gave signals of <_ 5% of the basal signal. Other primary antibodies to murine PECAM-1 suitable for FACS ® analysis in combination with a labelled secondary antibody are available from, e.g., Santa Cruz Biotechnology (Santa Cruz, CA) ; Endogen (formerly T Cell Diagnostics, Woburn, MA) ; PharMingen (San Diego, CA) ; and Paesel & Lorei (Hanau, Germany) . The results (Table 12) demonstrate that the control (scrambled) oligonucleotide was not capable of modulating PECAM-1 expression (5% inhibition) whereas the active compound, ISIS 13989, caused about 50% inhibition. Thus, the PECAM-1-modulating activity of the active antisense compounds is sequence-specific. D. Time Course: The time course of inhibition of PECAM-1 mRNA expression in bEND.3 cells following treatment with 300 nM of ISIS 13989, 13991 and 13995, as measure by FACS ® analysis, is shown in Table 13. Twenty-four hours after treatment with ISIS 13989, the level of inhibition of murine PECAM-1 was about 39% (t=24 h) , rose to about 70% inhibition at t=48 h, and subsequently decreased to about 15% at t=72 h, where "about" indicates ± 5%. A similar temporal pattern of modulation was seen for ISIS 13991 and 13995. E. Dose Response: The dose response of PECAM-1 protein expression in bEND.3 cells following treatment with various 100 - concentrations of ISIS 13989, 13991 or 13995 is shown in Table 14. Levels of PECAM-1 protein were determined by FACS C . Under these conditions and at a concentration of 37.5 nM, ISIS 13989 caused about 40% inhibition, wnereas ISIS 13991 and 13995 caused about 20% inhibition, of PECAM-1 protein levels (where "about" indicates ± 5%) . For ISIS 13989, the degree of inhibition increased to about 50% at 75 nM, to about 60% at 150 nM and to about 70% at 300 nM. For ISIS 13991, the degree of inhibition increased to about 25% at 75 nM, to about 45% at 150 nM and to about 60% at 300 nM. For ISIS 13995, the degree of inhibition increased to about 30% at 75 nM and to about 60% at 150 nM and 300 nM. TABLE 11 Activities of Phosphorothioate Oligonucleotides Targeted to Murine PECAM-1 ISIS SEQ GENE TARGET REGION % mRNA % mRNA No ID EXPRESSINHIBINO ION TION basal LIPOFECTIN ® only 100% 0% 13983 31 ORF 82% 18% 13984 32 ORF 75% 25% 13985 33 5' -UTR 66% 34% 13986 34 5' -UTR 66% 34% 13987 35 AUG 125% 13988 36 ORF 64% 36% 13989 37 ORF 50% 50% 13990 38 ORF 37% 63% 13991 39 ORF 25% 75% 101 - 13992 40 ORF 37% 63% 13993 41 ORF 46% 54% 13994 42 ORF 45% 55% 13995 43 stop 34% 66% 13996 44 3' -UTR 47% 53% 13997 45 3' -UTR 88% 12% 13998 46 3' -UTR 92% 8% 13999 47 3' -UTR 107% 1 Oligonucleotide concentration = 200 nM, t=4h. T.ABLE 12 Sequence Specificity of Phosphorothioate .Antisense Oligonucleotides (ASOs) Targeted to Murine PECAM-1 ISIS SEQ ASO GENE % PROTEIN % PROTEIN No ID TARGET REGION EXPRESSION INHIBITION basal LIPOFECTIN ® only 100% 0% 13989 37 stop codon region 49% 51% 14449 50 13989-scrambled 95% 5% control 1 bEND.3 cells treated with 50 nM (final concentration) of indicated oligonucleotides; samples taken at t = 24h. 102 - TABLE 13 Time Course of Response of bEND .3 Cells to Murine PECAM-1 Antisense Oligonucleotides (ASOs) SEQ ASO Gene Target % o_ "0 ISIS # ID Region Time Protein Protein NO ExpressInhibition ion basal LIPOFECTIN ® only 24 h 100.0% 0.0% basal w 48 h 100.0% 0.0% basal 2 72 h 100.0% 0.0% 13989 37 ORF 24 h 60.8% 39.2% 13989 37 48 h 31.2% 68.8% 13989 37 \\ 72 h 85.1% 14.9% 13991 39 ORF 24 h 64.7% 35.3% 13991 39 48 h 34.2% 65.8% 13991 39 \\ 72 h 97.3% 2.7% 13995 43 stop codon 24 h 52.7% 47.3% 13995 43 w 48 h 28.4% 71.6% 13995 43 \\ 72 h 83.0% 17.0% 1 bEND.3 cells treated with 300 nM (final concentration) of indicated oligonucleotides. 2 Derived from two samples; all other data points are averages (means) of determinations from three samples. 103 TABLE 14 Dose Response of Murine bEND .3 Cells to Murine PECAM-1 Antisense Oligonucleotides (ASOs) SEQ ASO Gene % % ISIS # ID Target Dose Protein Protein NO ExpressInhibition ion basal LIPOFECTIN ® only 0 nM 100 % 0% 13989 37 ORF 37.5 nM 59.6% 40.4% 13989 37 \\ 75 nM 46.9% 53.1% 13989 37 \\ 150 nM 39.5% 60.5% 13989 37 \\ 300 nM 34.7% 66.3% 13991 39 ORF 37.5 nM 80.5% 19.5% 13991 39 \\ 75 nM 76.5% 23.5% 13991 39 \\ 150 nM 55.0% 45.0% 13991 39 \\ 300 nM 38.5% 61.5% 13995 43 stop codon 37.5 nM 80.0% 20.0% 13995 43 75 nM 68.8% 31.2% 13995 43 w 150 nM 39.2% 60.8% 13995 43 w 300 nM 44.0% 56.0% 1 t=48h. Ex.ample 7 : A tisense-Mediated Inhibition of Murine PECAM- 1 Expression by Second Generation Oligonucleotides A. Design of "Second Generation" Human PECAM-1 oligonucleotides: Results from the murine PECAM-1-specific phosphorothioate oligonucleotides indicate that one of the preferred phosphorothioate oligonucleotides for modulating - 104 - PECAM-1 expression is ISIS 13989 (SEQ ID NO: 37) . "Second generation" oligonucleotides having the same nucleobase sequence as ISIS 13989 but having additional chemical modifications were designed and synthesized to confirm and extend these findings. As detailed m Table 4, ISIS 17050, 17051, 17052, 17053 and 20380 are "gapmers" having the same nucleobase sequence as ISIS 13989; all of these oligonucleotides have 2 ' -methoxyethoxy flanks or "w gs" and a central 2 ' -deoxy "gap" designed to support RNase H activity on the target mRNA molecule. ISIS 17049 and 17054 are hemimers having the same nucleobase sequence as ISIS 13989 and having a 2 ' -methoxyethoxy, RNase H-refractory 3' or 5 ' first portion and a 5' or 3 ' , respectively, second portion (the "wing") that comprises 2 ' -deoxy residues. Like the central "gap" portion of the gapmers, the second, 2 ' -deoxy portion of the hemimer oligonucleotides is designed to support RNase H activity on the target PECAM-1 mRNA. The 2'- ethoxyethoxy portions ("wmgs") of these oligonucleotides also contain 5-methyl-cytιdme (m5C) residues. B. Activities of Second Generation Murine PECAM-1 Oligonucleotides: The chemically modified derivatives of ISIS 13989 (SEQ ID NO: 37) were tested in the PECAM-1 protein assay (FACS ® ) described above with the following modifications: oligonucleotides were added to cells to a final concentrations of 50 nM, and samples were taken for analysis at 24 h. The results are presented Table 15. Because of their ability to modulate PECAM-1 expression to the same or greater degree than the parent phosphorothioate antisense compound ISIS 13989 (as reflected by levels of inhibition from about 50% to 100% of PECAM-1 levels at t=24h, where "about" indicates ± 5%), the chemically modified antisense oligonucleotides targeted to murine PECAM-1 are preferred embodiments of the invention. Preferred are ISIS 17049, 17050, 17051, 17052, 17053 and 105 - 17054. Particularly preferred are those antisense compounds causing levels of inhibition from ≥ aoout 70% to 100% of PECAM-1 levels at t=24h, i.e., ISIS 17050, 17051, 17052 and 17053. TABLE 15 Activity of "Second Generation" Antisense Oligonucleotides Targeted to Murine PECAM-1 ISIS SEQ GENE TARGET REGION % PROTEIN % No ID EXPRESSPROTEIN NO ION INHIBITION basal — LIPOFECTIN ® only 100% 0% 13989 37 stop codon region 49% 51% (phosphorothioate) 17049 37 13989-derιved 44% 56% 3 ' -hemimer 17050 37 13989-derιved 25% 75% gapmer 17051 37 13989-deπved 28% 72% gapmer 17052 37 13989-derιved 32% 68% gapmer 17053 37 13989-derιved 33% 67% gapmer 17054 37 13989-deπved 40% 60% 5 ' -hemimer - bEND.3 cells treated with 50 nM (final concentration) of indicated oligonucleotides; samples taken at t = 24h. - 106 - Ex.am.ple 8 : Animal Model for Antisense Modulation of PECAM-1 The present invention provides compositions and methods for modulating the transmigration of leukocytes and thus controlling related undesirable immune responses such as, e.g., inflammation. In order to test the ability of the antisense compounds of the invention to mo^dulate cellular transmigration, a variation of the thioglycollate-induced peritonitis model of Watson et al . { Na ture, 1991, 349, 164; see also Liao et al . , J. Exp . Med. , 1997, 185, 1349, and Bogen et al . , J. Exp . Med. , 1994, 175, 1059) was used in which lipopolysaccharide (LPS) is substituted for thioglycollate . Groups (n=5 per group) of female C57 Black 6 mice were given saline or various doses (0.3, 1, 3, 10 or 30 mg/kg) of antisense oligonucleotide by i.v. daily for seven days and then challenged with 25 ug of LPS from Salmonella typhosa (DIFCO laboratories, Livonia, MI) per mouse given i.p. Peritoneal lavages were performed 18 hours later and cells were prepared using CYTOSPIN cytocentrifuges (Shandon Lipshaw, Pittsburgh, PA) . To determine the proportion of polymorphonuclear neutrophil granulocytes (PMNs) present in the peritoneal fluid, the cells were stained with Wright/Giemsa stain (Sigma Chemical Co., St. Louis, MO) and different cell types, including PMNs, were counted. The results (Table 16) indicate that treatment with ISIS 13989 (SEQ ID NO: 37) reduced the transmigration of PMNs into the peritoneal fluid. Specifically, at a dose of 3 mg/kg, the absolute percentage of PMNs decreased to about 70%, where "about" indicates ± 5%. At doses of 10 and 30 mg/kg, animals treated with ISIS 13989 had peritoneal PMN percentages of about 40% and 25%, respectively. In contrast, animals treated with ISIS 14449, a scrambled control for ISIS 13989, showed PMN levels of about 65% and 55% at doses of 3 and 30 mg/kg, respectively. These results demonstrate the ability of the - 107 - antisense compounds of the invention to modulate the transmigration of leukocytes and related undesired immune responses . TABLE 16 Activity of PECAM-1-Modulating Antisense Compounds in Animal Model of Peritonitis Number of PMNs Relative ISIS No. Dosinσ Schedule in Peritoneum Response (saline) i.v. daily x 7 days 1.3 x 10 1.00 13989 0.3 mg/kg (as above) 1.2 x 10' 0.92 13989 1.0 mg/kg (as above] 1.3 x 10 ( 1.00 13989 3.0 mg/kg (as above) 9.0 x 10' 0.69 13989 10 mg/kg (as above) 5.1 x 10 s 0.39 13989 30 mg/kg (as above) 3.4 x 10 s 0.26 14449 3.0 mg/kg (as above) 8.3 x IO 5 0.63 14449 30 mg/kg (as above) 7.1 x IO 5 0.54 Example 9 : Therapeutic Methods The antisense compounds of the invention result in immunosuppressive and anti-inflammatory effects in vivo and may be used by those skilled in the art to provide - 108 - prophylactic, palliative and therapeutic benefit to an animal, including a human, in need of such effects. The antisense compounds of the invention are also evaluated for their ability to inhibit the metastasis of cancer cells and are used to provide prophylactic, palliative or therapeutic relief from hyperproliferative disorders. Therapeutic methods using the antisense compounds of the invention include, but are not limited to, the following examples. A. Modulation of Undesirable Immunoresponsive Events: The present invention provides a method of modulating immunoresponsive events that are mediated or influenced, either directly or indirectly, by PECAM-1 in an animal. Such immunoresponsive events can lead to undesirable effects such as, e.g., inflammation. The method of modulating immunoresponsive events mediated or influenced by PECAM-1 comprises administering one or more of the antisense compounds of the invention (or a combination thereof with one or more anti-inflammatory or immunosuppressive non-antisense-based agents or NABAs; see below), in a pharmaceutical preparation if required, to the animal. Some specific therapeutic modalities for the antisense compounds of the invention follow as examples but are not intended to limit the scope of the invention . 1. Diapedesis: The present invention provides a method of modulating PECAM-1-mediated diapedesis in an animal comprising administering one or more of the antisense compounds of the invention, or a combination thereof with one or more anti-inflammatory or immunosuppressive agents, in a pharmaceutical preparation if required, to the animal. Diapedesis, the transendothelial migration of immunoresponsive cells (such as leukocytes) from the circulatory system into injured or infected tissues, is thought to be a key event in inflammatory injury (for a review, see Albelda et al . , FASEB - 109 - J. , 1994, 8, 504). Several lines of evidence suggest that PECAM-1 is particularly important for the diapedesis of some cells such as leukocytes (white blood cells), which include, for example, polymorphonuclear neutrophil granulocytes (PMNs or neutrophils) and some macrophages such as monocytes, and lymphocytes such as natural killer (NK) cells and T lymphocytes (T cells) . First, antibodies to PECAM-1 block the transmigration of neutrophils (Vaporciyan et al . , Science, 1993, 262, 1580), monocytes (Muller et al . , J. Exp . Med. , 1993, 1 78, 449; Shen et al . , Am . J. Physiol . , 1996, 270, H1624), leukocytes (Muller, Agen ts Actions Suppl . , 1995, 46, 147) and NK cells (Berman et al . , J. Immunol . , 1996, 156, 1515) . Second, a polypeptide corresponding to a portion of PECAM-1 blocks transendothelial migration of PMNs and monocytes both in vi tro and m vivo (Liao et al . , J. Exp . Med. , 1997, 185, 1349) . Administration of the antisense compounds of the invention, as part of an appropriate pharmaceutical composition if required, to an animal is expected to inhibit diapedesis and subsequent undesired immunoresponsive events such as, for example, inflammation and inflammatory damage. Such treatment may be combination with one or more anti-mflammatory and/or immunosuppressive NABAs and, additionally or alternatively, with one or more additional antisense compounds targeted to, for example, a CAM protein, a B7 protein, or a protein kinase C (see below) . Such administration can be systemic or directly to the sιte(s) of diapedesis, inflammation and/or inflammatory damage. The antisense compounds of the invention are evaluated for their ability to modulate diapedesis and subsequent undesired inflammation and/or inflammatory damage using, for example, the assays described in the references cited this section, the m vi tro flow model of Luscmskas et al . ( J. Immunol . , 1996, 157, 326), the mouse model using carrageenan-soaked - 110 - sponges described in Example 22 of U.S. Patent No. 5,514,788 to Bennett et al . (hereby incorporated by reference) and/or other relevant animal models. 2. Acute Inflammation: The present invention also provides a method of modulating acute inflammation, such as occurs in peritonitis, in an animal comprising administering one or more of the antisense compounds of the invention, or a combination thereof with one or more anti-mflammatory or immunosuppressive agents, in a pharmaceutical preparation if required, to the animal. A murine monoclonal antibody to PECAM-1 blocks acute inflammation an in vivo (murine) model of peritonitis (Bogen et al . , J. Exp . Med. , 1994, 1 79, 1059) and, similarly, a rabbit polyclonal antibody inhibits leukocyte transmigration m glycogen- duced peritonitis m cats (Murohara et al . , J. Immunol . , 1996, 156, 3550). Administration of the antisense compounds of the invention, as part of an appropriate pharmaceutical composition if required, to an animal is expected to inhibit undesired acute inflammation and resulting inflammatory damage. Such administration can be systemic or directly to the sιte(s) of inflammation. Such treatment may be m combination with one or more anti-mflammatory and/or immunosuppressive NABAs and, additionally or alternatively, with one or more additional antisense compounds targeted to a CAM protein, a B7 protein, or a protein kinase C (see below) . The antisense compounds of the invention are evaluated for their ability to modulate acute inflammation and subsequent events using, for example, the assays described in the reference cited in this section or known in the art and/or appropriate animal models . 3. Corneal Inflammation: The presenc invention also provides a method of treating corneal inflammation m an animal comprising administering one or more of the antisense compounds of the invention, or a combination thereof with one - Ill - or more anti-mflammatory or immunosuppressive agents, in a pharmaceutical preparation if required, to the animal. PECAM- 1 has been stated to be found at zones of marked inflammation in specimens from a broad range of corneal inflammatory diseases (Goldberg et al . , Opthamology, 1994, 101 , 161). Administration of the antisense compounds of the invention, as part of an appropriate pharmaceutical composition if required, to an animal is expected to inhibit undesired corneal inflammation and resulting inflammatory damage. Such administration can be systemic or directly to the cornea (s) exhibiting inflammation. Such treatment may be in combination with one or more anti-mflammatory and/or immunosuppressive NABAs and, additionally or alternatively, with one or more additional antisense compounds targeted to a CAM protein, a B7 protein, or a protein kinase C (see below) . The antisense compounds of the invention are evaluated for their ability to modulate corneal inflammation and subsequent events using one or more assays known the art and/or one or more appropriate animal models. 4. Allograft Rejection and GVHD: The present invention also provides a method of avoiding allograft rejection including treating or preventing graft versus host disease (GVHD) in an animal comprising administering one or more of the antisense compounds of the invention, or a combination thereof with one or more anti-mflammatory or immunosuppressive agents, in a pharmaceutical preparation if required, to the animal. At least one study suggests that nucleic acids encoding human PECAM-1 are polymorphic, and that, when donor and recipient PECAM-1 genotypes are not matched in bone marrow transplants, the risk of acute GVHD increases (Behar et al . , New England J. Med. , 1996, 334, 286). Accordingly, administration of one or more of the PECAM-1- modulat g antisense compounds of the invention (in - 112 - combination with other agents and as part of an appropriate pharmaceutical composition if required) to an animal is expected to modulate allograft rejection and GVHD. Such administration can be systemic or directly to the area(s) of the transplanted tissue (s) or organ (s), or administered ex vivo to tissue (s) or organ (s) prior to their transplantation. Such treatment may be in combination with one or more anti-mflammatory/immunosuppressive NABAs and, additionally or alternatively, with one or more additional antisense compounds targeted to a CAM protein, a B7 protein, or a protein kinase C (see below) . The antisense compounds of the invention are evaluated for their ability to modulate allograft rejection using one or more assays known in the art and/or one or more appropriate animal models (see, e.g., Stepkowski et al . , J. Immunol . , 1994, 153, 5336, and Example 21 U.S. Patent No. 5,514,788 to Bennett et al . , hereby incorporated by reference) . 5. Arthritis: The present invention also provides a method of treating various forms of arthritis in an animal comprising administering one or more of the antisense compounds of the invention, or a combination thereof with one or more anti-mflammatory or immunosuppressive agents, a pharmaceutical preparation if required, to the animal. Such administration can be systemic or directly to involved tissues such as, e.g., synovial fluid. Increased expression of CAMs, including ELAM-1, VCAM-1, ICAM-1 and PECAM-1 has been detected m synovial fluid from patients having rheumatoid arthritis (Tak et al . , Cl m . Immunol . Immunopa thol . , 1995, 77, 236) . Such forms of arthritis include, for example, autoimmune forms of arthritis, including some forms of rheumatoid arthritis (RA) , psoπatic arthritis (PA) and ankylosmg spondylitis (AS); non-autoimmune forms of RA, PA and AS; infectious arthritis, such as results from infection with spirochetes - 113 - (Ly e disease, also known as LD or Lyme arthritis, is caused by Borrel ia burgdorferi , and some instances of Reiter' s syndrome, RS, appear to be associated with Chlamydia tra choma tis ) , bacterial infection (staphylococci such as Hemophil us mfl uenzae, streptococci, pneumococci, gram- negative bacilli and the like), viral infection (e.g., rubella, mumps, human parvovirus or hepatitis B) , and/or fungal infection (e.g., Sporothrix schenckn , Coccidioides immi tis , Blastomyces derma tididis or Candida albicans ) (see The Merck Manual of Diagnosis and Therapy, 15th Ed., pp. 1239- 1267, Berkow et al . , eds., Rahay, N.J., 1987). Such treatment may be in combination with one or more additional antisense compounds or anti-mflammatory/immunosuppressive NABAs and, additionally or alternatively, when the arthritis to be treated results at least part from infection of the animal by a pathogen, with one or more antibiotics (see below) . The antisense compounds of the invention are evaluated for their ability to modulate arthritis and inflammatory damage resulting therefrom using one or more assays known in the art and/or one or more appropriate animal models (see, e.g., published PCT application No. WO 95/32285 to Benoist et al . ) . 6. Infl.ammatory Disorders of the Bowel: The present invention also provides a method of treating various inflammatory disorders of the bowel in an animal comprising administering one or more of the antisense compounds of the invention, or a combination thereof with one or more anti- mflammatory or immunosuppressive agents, in a pharmaceutical preparation if required, to the animal. Such disorders include, for example, Crohn' s disease (CD) and other forms of regional enteritis; and various forms of colitis including ulcerative colitis (UC) and granulomatous, lschemic and radiation colitis (see The Merck Manual of Diagnosis and Therapy, 15th Ed., pp. 797-806, Berkow et al . , eds., Rahay, - 114 - N.J., 1987) . Such treatment may be m combination with one or more additional antisense compounds or anti-mflammatory and/or immunosuppressive NABAs (see below) . The antisense compounds of the invention are evaluated for their ability to modulate a inflammatory disorder of the bowel using one or more assays known in the art and/or one or more appropriate animal models (see, e.g., Okayasu et al . , Gas troenterol . , 1990, 98, 694, and Example 20 m U.S. Patent No. 5,514,788 to Bennett et al . , hereby incorporated by reference) . 7. Autoimmune Diseases and Disorders: The present invention also provides a method of treating various autoimmune diseases and disorders including but not limited to autoimmune thyroid disorders; autoimmune forms of arthritis; multiple sclerosis (MS); some forms of juvenile diabetes mellitus; myasthenia gravis; pemphigus vulgaris; and systemic lupus erythematosus (SLE or lupus) (for a review of autoimmune disorders, see Ste man, Sci . Amer . , 1993, 269, 107) . A preferred embodiment of the invention involves the treatment or prevention of autoimmune thyroid disorders, such as, e.g., Graves' Disease (thyrotoxicosis ) , Hashimoto's disease and De Quervam thyroiditis, as PECAM-1 has been observed to be expressed on cells involved in such conditions (Marazuela et al . , Clm . Exp . Immunol . , 1995, 102, 328; Aubert et al . , Clm . Immunol . Immunopa thol . , 1995, 76, 170) . Administration of the antisense compounds of the invention, as part of an appropriate pharmaceutical composition if required, to an animal is expected to prevent or inhibit the development of the autoimmune disease and subsequent undesired events. Such treatment may be m combination with one or more anti-mflammatory/immunosuppressive NABAs and, additionally or alternatively, with one or more additional antisense compounds targeted to, for example, a CAM protein, a B7 protein, or a protein kinase C (see below) . Such - 115 - administration can be systemic or directly to a specific tissue, depending on the nature of the disorder. For example, systemic administration might be more appropriate for SLE, whereas direct administration to the thyroid gland or adjacent tissues might be more efficacious in the case of Graves' Disease. The antisense compounds of the invention are evaluated for their ability to prevent or inhibit autoimmune diseases using appropriate assays and animal models known to those skilled in the art (see, for example, Burkhardt et al . , Rheuma tol . In t . , 1997, 17, 91) . B. Cardiovascular Disorders: The present invention provides a method of modulating undesirable events that are mediated or influenced, either directly or indirectly, by PECAM-1 in an animal during or following cardiovascular injury or during the course of a cardiovascular disease or disorder. The method of modulating immunoresponsive events mediated or influenced by PECAM-1 comprises administering one or more of the antisense compounds of the invention, in a pharmaceutical preparation if required, to the animal. Some specific therapeutic modalities for the antisense compounds of the invention follow as examples but are not intended to limit the scope of the invention. 1. Myocardial Ischemia/Reperfusion Injury: The present invention provides a method of reducing or preventing myocardial ischemia/reperfusion (MI/R) injury n an animal comprising administering one or more of the antisense compounds of the invention, or a combination thereof with one or more anti-inflammatory or immunosuppressive agents, in a pharmaceutical preparation if required, to the animal. Coronary artery reperfusion is an effective treatment for patients with acute myocardial infarction. However, reperfusion itself often leads to enhanced injury of myocardial tissue. Transmigration of PMNs into the lschemic - 116 - myocardium is believed to play some role m myocardial ischemia/reperfusion injury (Entman et al . , FASEB J. , 1991, 5, 2529; Lefer et al . , FASEB J. , 1991, 5, 2029). Antibodies to PECAM-1 attenuate MI/R injury m vivo in feline and rodent models (Gum a et al . , Circ , 1996, 94, 3327; Murohara et al . , J. Immunol . , 1996, 156, 3550) . Administration of the antisense compounds of the invention, as part of an appropriate pharmaceutical composition if required, to an animal is expected to modulate MI/R injury. Such administration can be systemic or directly to the circulatory system. Such treatment may be in combination with one or more additional antisense compounds targeted to, e.g., a CAM protein, a B7 protein, or a protein kinase C (see below) . The antisense compounds of the invention are evaluated for their ability to modulate MI/R injury using one or more assays known in the art and/or one or more appropriate animal models such as, for example, those described m the references cited in this section. 2. Stroke-Related Damage: The present invention provides method of reducing leukocyte-mduced damage m an animal during or following a stroke or series of strokes, or of preventing leukocyte-mduced damage from a stroke m an animal known to be prone to having strokes, m an animal comprising administering one or more of the antisense compounds of the invention, m a pharmaceutical preparation if required, to the animal. A stroke is a blockage or hemorrhage of a blood vessel m or leading to the brain (e.g., aneurys al subarachnoid hemorrhage) that causes inadequate blood supply (ischemia) to the brain. After brain ischemia, leukocytes adhere to the perturbed vascular endothelium and are believed to aggravate reperfusion injury eventually leading, some cases, to chronic vasospasm (i.e., a sudden constriction of an artery or vein) , which in turn can have - 117 - serious and undesired consequences. Adhesion molecules, including ICAM-1, are upregulated m acute infarctions from brain sections of human subjects who died within 18 days of ischemic stroke (Lmdsberg et al . , Circ , 1996, 94 , 939). In an animal model, a monoclonal antibody to ICAM-1 inhibited vasospasm (Oshiro et al . , Stroke, 1997, 28, 2031). Administration of the antisense compounds of the invention, as part of an appropriate pharmaceutical composition if required, to an animal is expected to stroke-related injuries. Such administration can be systemic or directly to the circulatory system. Such treatment may be in combination with one or more additional antisense compounds targeted to a CAM protein, a B7 protein, or a protein kinase C (see below) . Alternatively, in this method of the invention, compounds targeted to a CAM protein, a B7 protein, or a protein kinase can be used without an antisense compound targeted to PECAM-1, or in combination with each other. The antisense compounds are evaluated for their ability to modulate stroke-related injury using one or more assays known in the art and/or one or more appropriate animal models such as, for example, those described in the references cited in this section. C. Treatment of Hyperproliferative Disorders: Patients having benign tumors, and primary malignant tumors that have been detected early in the course of their development, may often be successfully treated by the surgical removal of the benign or primary tumor. If unchecked, however, cells from malignant tumors are spread throughout a patient's body through the processes of invasion and metastasis. Invasion refers to the ability of cancer cells to detach from a primary site of attachment and penetrate, e.g., an underlying basement membrane. Metastasis indicates a sequence of events wherein (1) a cancer cell detaches from its extracellular matrices, (2) the detached cancer cell migrates to another portion of - 118 - the patient's body, often via the circulatory system, and (3) attaches to a distal and inappropriate extracellular matrix, thereby creating a focus from which a secondary tumor can arise. Normal cells do not possess the ability to invade or metastasize and/or undergo apoptosis (programmed cell death) if such events occur (Ruoslahti, Sci . Amer . , 1996, 275, 72) . Disseminating precancerous or cancerous cells often display ectopic expression of adhesion molecules which may facilitate step (3) of the metastatic process as described above. Examples of such adhesion molecules include ICAM-1, PECAM-1 and other CAMs (for a review, see Tang et al . , Invasion Metastasis, 1994, 14 , 109). Thus, modulation of one or more CAMs using the antisense compounds of the invention may result in a decreased ability of disseminating cancer cells to attach to a distal and/or inappropriate matrix, thereby modulating metastasis of the primary tumor. Moreover, because PECAM-1 apparently also helps regulate the expression and/or activity of other molecules involved m cell-cell interactions (Litwin et al . , J. Cell Biol . , 1997, 139, 219), modulation of PECAM-1 by the oligonucleotides of the present disclosure will also result in the modulation of expression of molecules involved in cell-cell interactions, further limiting the metastatic ability of tumors . The present invention thus also provides a method of modulating or preventing metastasis m an animal comprising administering one or more of the antisense compounds of the invention, a pharmaceutical preparation if required, to the animal. Such treatment may be combination with one or more additional antisense compounds or anticancer chemotherapeutic NABAs (see below) . The antisense compounds of the invention are evaluated for their ability to modulate metastasis using one or more assays known m the art and/or one or more appropriate animal models (see, e.g., Examples 16-18 m U.S. - 119 - Patent No. 5,514,788 to Bennett et al . , hereby incorporated by reference) . As another example, cell line number CRL-11448 from the American Type Culture Collection (Rockville, MD) is an PECAM-1/CD31 + endothelial cell line derived from a patient with Kaposi's sarcoma that forms metastatic tumors in immunodeflcient mice. CRL-11448 can be used to evaluate the ability of the PECAM-1-targeted antisense compounds of the invention to modulate metastatic events in vivo . D. Modulation of aberrant angiogenesis: Angiogenesis, the development of new blood vessels from existing vessels, is a requirement of tumor growth, because tumors cannot grow beyond a minuscule size, cr metastasize, without tne formatio n or new blood vessels zo support the nutritional requirements of the tumor tissue. Angiogenesis inhibitors are being evaluated for use as antitumor drugs. Uncontrolled angiogenesis can also occur in the eye, causing loss of vision. Examples of this include retmopathy of prematurity, diabetic retmopathy, and other vascular occlusive diseases of the eye. Excessive angiogenesis also occurs in the synovial tissue of patients with rheumatoiα arthritis, and psoπatic lesions Thus inhibition of angiogenesis using PECAM-^ as a tarσet is desired. In certain other conditions, increased angiogenesis is desired; for example, to circumvent vessels blocked by atherosclerosis. Thus "aberrant" angiogenesis can refer to excessive or insufficient angiogenesis, or undesired angiogenesis (as, for example, the case of angiogenesis which supports tumor growth) . E. Combination Therapies and Compositions If desired, the therapeutic antisense modulation of the expression of PECAM-1 (or another CAM) can be combined with additional therapies order to achieve a requisite ^ .evel of interference with, or prevention of, undesirable disorders or SUBSTπUTESHEET(RULE26) - 120 - diseases. Such combinations can be carried out, for example, by simultaneously administering (a) two or more antisense compounds targeted to two or more CAMs, (b) two or more antisense compounds, one targeted to a CAM and one another genetic target or (c) , when treating an animal having inflammation, an antisense compound targeted to a CAM in combination with a non-antisense-based anti-mflammatory or immunosuppressive agent. If an animal having a hyperproliferative disease or disorder is to be treated, the antisense compound targeted to a CAM may be combined with a non-antisense-based chemotherapeutic agent. When used with the antisense compounds of the invention, such non-antisense- based agents (NABAs) may be used in simple combination (e.g., administration of a NABA and an antisense compound) , sequentially (e.g., administration of a first NABA and an antisense compound for a period of time followed by administration of a second NABA and an antisense compound) , or in combination with one or more other such non-antisense- based agents or physical treatments (e.g., administration of a NABA and an antisense compound, or, in the treatment of hyperprolif rative disorders for example, administration of one or more NABAs and antisense compounds combination with radiotherapy) . When two (or more) antisense compounds, or a combination of one or more antisense compounds and one or more NABAs, are to be administered simultaneously m a treatment regime, one preferred composition is one comprising a lipid vesicle, particularly a sterically stabilized lipid vesicle, comprising both (or all) of the compounds. In the context of the invention, the term "treatment regimen" is meant to encompass therapeutic, palliative and prophylactic modalities. 1. Combinations of .Antisense Compounds : Two or more antisense compounds can be administered simultaneously as described above. Combination treatments can also be carried - 121 - out by first (1) administering a first composition comprising one or more antisense compounds targeted to one or more CAMs (or a combination thereof with one or more anti- mflammatory/immunosuppressive or chemotherapeutic agents) for a first period of time and then (2) "switching" to administration of a second composition comprising one or more antisense compounds targeted to one or more CAMs (or a combination thereof with one or more anti-mflammatory or chemotherapeutic agents) for a second period of time. Whether administered simultaneously or sequentially, preferred pairings of antisense compounds include those targeted to molecules that mediate cellular adhesion, such as: (1) PECAM-1 and ICAM-1; (2) PECAM-1 and VCAM-1; (3) PECAM-1 and ELAM-1; (4) PECAM-1 and a B7 protein, such as B7-1 or B7-2; (5) ICAM-1 and VCAM-1; (6) ICAM-1 and ELAM-1; (7) ICAM-1 and a B7 protein; (8) VCAM-1 and ELAM-1; (9) VCAM-1 and a B7 protein; (10) ELAM-1 and a B7 protein. Antisense compounds targeted to ICAM-1, VCAM-1, ELAM-1 and B7 proteins are described U.S. Patents Nos. 5,514,788 and 5,591,623, and copendmg U.S. patent application Serial No. 08/777,266, filed December 31, 1996, all to Bennett et al . Because protein kinase C (PKC) appears to be required for, or at least involved m, PECAM-1 phosphorylation and activation (Zehnder et al . , J. Biol . Chem . , 1992, 2*57, 5243; Lastres et al . , J. Immunol . , 1994, 153, 4206; Shen et al . , Am . J. Physiol . , 1996, 270 { Heart Circ . Physiol . , 39) , H1624), combinations of the PECAM-1-targeted antisense compounds of the invention and antisense compounds targeted to PKC may be particularly effective and are a preferred embodiment of the invention. Antisense compounds targeted to PKC are described m U.S. Patents Nos. 5,620,963 to Cook et al . and 5,681,747 to Boggs et al . NABAs that inhibit PKC, such as, e.g., staurosporm, may additionally or alternatively be used m - 122 - combination with the antisense compounds of the invention. One skilled m the art can prepare and test more complex combinations of antisense compounds, i.e., methods and compositions such as those described above but wherein three or more antisense compounds are administered. 2. Combinations with Chemotherapeutic Agents : For the purpose of treating hyperproliferative disorders, the antisense compounds of the invention can additionally or alternatively be used m combination with non-antisense-based chemotherapeutic agents. Examples of such agents that can be used in combination with the antisense compounds of the invention include but are not limited to daunorubicin, daunomycm, dact omycm, doxorubic , epirubic , ldarubic , esorubic , bleomycm, mafosfamide, ifosfamide, cytosine arabmoside, bis-chloroethylnitrosurea, busulfan, mitomycm C, actmomycm D, mithramycm, prednisone, hydroxyprogesterone, testosterone, tamoxifen, dacarbazme, procarbazme, hexamethylmelamme, pentamethylmelamme, mitoxantrone, amsacrme, chlorambucil, nitrogen mustards, methylcyclohexylnitrosurea, melphalan, cyclophosphamide, 6- mercaptopuπne, 6-thιoguanme, cytarabine (CA) , 5-azacytιdme, hydroxyurea, deoxycoformycm, 5-fluorouracil (5-FU), 4- hydroxyperoxycyclophosphoramide, 5-fluorodeoxyuridme (5- FUdR) , methotrexate (MTX) , colchicme, v cristme, vmblastme, etoposide, trimetrexate, teniposide, cisplatm and diethylstilbestrol (DES) . (See, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed., pp. 1206-1228, Berkow et al . , eds., Rahay, N.J., 1987). 3. Combinations with Anti-Inflammatory/lmmuno- suppressive Agents: Examples of non-antisense-based anti- mflammatory or immunosuppressive agents that can be used in combination with the antisense compounds of the invention include but are not limited to salicylates; nonsteroidal anti- - 123 - inflammatory drugs (NSAIDs), including indomethacin, ibuprofen, fenopofen, ketoprofen, naproxen, piroxicam, phenylbutazone, oxyphenbutazone, sulindac and meclofenamate; gold compounds, such as auranofin; D-penicillamine; cyclophosphamide; methotrexate; azathioprine; colchicine; hydroxychloroquine ; corticotropin; steroids and corticosteroids such as, for example, hydrocortisone, deoxyhydrocortisone, fludrocortisone , prednisolone, methylprednisolone, prednisone, triamcinolone, dexamethasone, betamethasone and paramethasone . See, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed., pp. 1239-1267 and 2497-2506, Berkow et al . , eds., Rahay, N.J., 1987). 4. Combinations with .Antibiotics: Some forms of arthritis result from infection of an animal by a pathogen, such as a bacteria or spirochete, and subsequent immune system-mediated events, e.g., inflammation. An observation that may at least partially explain such undesirable immune responses is that extracts of the arthritis-related spirochete Borrelia burgdorferi induce the upregulation of several cellular adhesion molecules (including ICAM-1, VCAM-1, E- selectin and P-selectin) on bEND.3 cells, an effect that is blocked by the anti-inflammatory agent prednisolone (Hurtenbach et al . , In t . J. Immunopharma col . , 1996, 1 8, 281; Boggemeyer et al . , Cell . Adhes . Commun . , 1994, 2, 145). The present invention provides a method of treating spirochetal infection of an animal comprising administering one or more of the antisense compounds of the invention to an animal, in a pharmaceutical preparation if required. If the undesired inflammation results from infection from a pathogen one or more antibiotics may also be used in combination with an antisense compound of the invention with or without an anti-inflammatory or immunosuppressive agent. The choice of antibiotic (s ) to be used will depend on the - 124 - nature of the pathogen(s) (i.e., bacteria such as cocci, bacilli, etc. or spirochetes) . Such antibiotics include but are not limited to nafcillin (gram-positive cocci); penicillin G (gram-negative cocci) ; gentamicin and/or piperacillin (gram- negative bacilli); and one or more tetracyclines, one or more penicillin derivatives, erythromycin, doxycylcine, chloramphenicol and/or streptomycin (spirochetes such as, e.g., Borrelia burgdorferi and Treponema pall idum) . See, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed., pp. 132-136, 236-243, 1239-1267 and 1918-1919, Berkow et al . , eds., Rahay, N.J., 1987) . One skilled in the art will appreciate that, depending on the cause and stage of development of an undesired immune response resulting from pathogenic infection, it may be preferable in some instances to administer, either simultaneously or sequentially, more complex combinations. That is, the present invention encompasses more complex compositions and treatment regimes such as those comprising, for example, (1) one or more antisense compounds targeted to one or more CAMs, (2) one or more antibiotics, and (3) one or more anti- inflammatory/immunosuppressive NABAs .

Claims: - 125 - What is claimed is : 1. An antisense compound consisting of 8 to 30 nucleobases connected by covalent linkages, wherein said antisense compound has a nucleobase sequence specifically hybridizable with a region of a nucleic acid encoding a human platelet endothelial cell adhesion molecule 1, wherein said region is selected from the group consisting of the 5'- untranslated region, the open reading frame, the stop codon region and the 3 ' -untranslated region and wherein said antisense compound modulates the expression of said human platelet endothelial cell adhesion molecule 1. 2. The antisense compound of claim 1 wherein said nucleobase sequence of said antisense compound has SEQ ID NO: 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 19, 20, 21, 22, 23, 24, 25 or 26. 3. The antisense compound of claim 1 wherein said region is the stop codon region and wherein said nucleobase sequence specifically hybridizes to a sequence contained withm SEQ ID NO: 55 or 68. 4. The antisense compound of claim 3 wherein said nucleobase sequence comprises the sequence 5 '-GTGCATC, 5'- TGGCC or a sequence having SEQ ID NO: 58, 59 or 60. 5. The antisense compound of claim 1 wherein said region is the 3 ' -untranslated region and wherein said nucleobase sequence specifically hybridizes to a sequence contained within SEQ ID NO: 62, 64 or 66. - 126 - 6. The antisense compound of claim 5 wherein said nucleobase sequence comprises a sequence having SEQ ID NO: 65 or 67. 7. An antisense compound consisting of up to 30 nucleobases connected by covalent linkages, wherein said antisense compound has a nucleobase sequence which is specifically hybridizable with the start codon region of a nucleic acid encoding a human platelet endothelial cell adhesion molecule 1, and wherein said nucleobase sequence comprises at least an 8-nucleobase portion of SEQ ID NO: 5 which modulates the expression of said human platelet endothelial cell adhesion molecule 1. 8. A method of modulating the expression of human platelet endothelial cell adhesion molecule 1 in a cell comprising contacting said cell with an antisense compound of claim 1. 9. A pharmaceutical composition comprising an antisense compound or a bioequivalent thereof comprising from about 8 to about 30 nucleobases connected by covalent linkages, wherein said antisense compound comprises a nucleobase sequence specifically hybridizable with a region of a nucleic acid encoding a human platelet endothelial cell adhesion molecule 1 and wherein said antisense compound modulates the expression of said human platelet endothelial cell adhesion molecule 1, or one or more bioequivalents thereof. 10. The pharmaceutical composition of claim 9 wherein said nucleobase sequence is SEQ ID NO: 5. - 127 - 11. A method of treating or preventing a condition associated with the expression of a human platelet endothelial cell adhesion molecule 1 comprising administering to a human having or susceptible to said condition a therapeutically or prophylactically effective amount of the pharmaceutical composition of claim 9. 12. The method of claim 11 wherein said condition is diapedesis, an undesired immune response, a cardiovascular disorder or a hyperproliferative disorder. 13. The method of claim 12 wherein said undesired immune response is inflammation, an inflammatory disorder of the bowel, allograft rejection, graft versus host disease, arthritis or an autoimmune disease or disorder. 14. The method of claim 12 wherein said cardiovascular disorder is aberrant angiogenesis.

Inventors: BENNETT C FRANK, CONDON THOMAS P, FLOURNOY SHIN CHENG, ZHANG HONG, BENNETT, C., FRANK, CONDON, THOMAS, P., FLOURNOY, SHIN, CHENG, ZHANG, HONG
Applicants: BENNETT C FRANK, CONDON THOMAS P, FLOURNOY SHIN CHENG, ISIS PHARMACEUTICALS INC, ZHANG HONG, BENNETT, C., FRANK, CONDON, THOMAS, P., FLOURNOY, SHIN, CHENG, ISIS PHARMACEUTICALS, INC., ZHANG, HONG
Application year: 1999
Main classification: C12Q1
IPC codes: A61K31, A61K38, A61K48, A61P1, A61P9, A61P19, A61P29, A61P35, A61P37, A61P43, C12N15, C12P19, C12Q1