COMPOSITIONS AND METHODS FOR TREATING TUMOR CELLS

Abstract: Antisense molecules, compositions thereof, and vectors encoding antisense RNA, and methods of using antisense molecules, compositions, and vectors for treating human glioblastoma cells in order to suppress the growth of the cells. The antisense molecules are substantially complementary to human fibroblast growth factor receptor gene one (the FGFR1).

Description: DESCRIPTION Compositions and Methods for Treating Tumor Cells This application is a continuation-in-part of United States Serial No. 08/371,001, filed January 10, 1995, the disclosure of which is incorporated herein by reference. Background of the Invention 1. Field of the Invention This invention relates to antisense molecules for suppressing the growth of tumor cells, and to methods for using the antisense molecules to suppress the growth of tumor cells. In particular, the invention is directed to compositions of antisense oligonucleotides and methods for suppressing the growth of glioblastoma cells. 2. Description of Related Art The publications and other reference materials referred to herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference. For convenience, the reference materials are numerically referenced and grouped in the appended bibliography. The vast majority of primary central nervous system tumors in humans are glial cell-derived neoplasms (gliomas or glioblastomas) . Most of these neoplasms derive from the astrocyte line of brain cells. Routine forms of cancer therapy, such as surgery, radiation therapy and chemotherapy are either not effective against human glioblastomas or are not specific for glioblastoma cells. As a result, the average survival time for a patient with glioblastoma multiforme is approximately 14 months. The vast majority (90%) of human glioblastomas are resistant to Traditional chemotherapeutic agents, such as the commonly used alkylating agents. Furthermore, these agents are not specific for cancer cells and inhibit the growth of any cell that is proliferating. As a result, these agents have many side effects. The same limitations apply to radiation therapy. There is presently no form of immunotherapy or gene therapy that is effective against human glioblastomas. Although the causes of astrocytic tumors remain obscure, the transformation of normal cells into cancerous ones and their progression into malignancy has been partially characterized at the biochemical level. It has been found that many malignant tissues produce an abnormally large amount of basic fibroblast growth factor (BFGF) , a protein which stimulates cells to divide and grow (1,2,3) . It is believed that the effects of BFGF are mediated through specific binding with fibroblast growth factor receptor proteins (FGFRs) . FGFRs are membrane bound proteins. Four structurally related genes encoding five high-affinity FGFRs have been identified (4-9) . FGF proteins and receptors have been identified in human glioma cells (10) , however, their role in glioblastoma growth and invasion of normal tissues is not understood. Antisense oligodeoxynucleotides are one example of a specific therapeutic tool with the potential for ablating oncogene function. These single-stranded synthetic oligonucleotides have a nucleoside base sequence complementary to the target pre-mRNA (heterogeneous nuclear RNA - hnRNA) or mRNA of a target gene and form a hybrid duplex by hydrogen bonded base pairing. The targeted RNA duplexed by forms of antisense oligonucleotide such as diesters, phosphorthioates, or phosphorodithioates is reportedly subject to RNaseH degradation in the duplexed region. Antisense oligonucleotides are thought to work by a cleavage mode of action or by stericaliy blocking enzymes involved in processing pre-mRNA or translation of mRNA. This hybridization of oligomer to RNA is thought to prevent or interfere with expression, i.e. translation of the target mRNA code into its protein product and thus preclude subsequent effects or prevent activity of the protein product. Because the mRNA sequence expressed by the gene is termed the sense sequence, the complementary sequence is termed the antisense sequence. Under some circumstances, degradation of mRNA would be more efficient than inhibition of an enzyme's active site, since one mRNA molecule may give rise to multiple protein copies. Synthetic oligodeoxynucleotides have been reported to inhibit production of c-myc protein, thus arresting the growth of human leukemic cells in vi tro (11) . Oligodeoxynucleotides have also been reported as specific inhibitors of retroviruses, including the human immunodeficiency virus (HIV-1) (12) . Attempts have been made using oligodeoxynucleotides to suppress bFGF expression, and inhibit growth of transformed human astrocytes in culture (13,14) . The mechanism of action by which these oligonucleotides achieve their effects is a matter of controversy. Accordingly, further developments are needed to develop a therapy that is specific for human glioblastoma tumors and which suppresses, inhibits, prevents or significantly reduces the growth of human glioblastoma cells as a means of curing, or at least improving the survival and morbidity associated with the occurrence of glioblastoma multiforme tumors in humans. SUMMARY OF THE INVENTION The claimed invention overcomes the above-mentioned problems, and provides antisense molecules, compositions of antisense molecules and a method of using the claimed molecules and compositions which provide the advantage of inhibiting, preventing, or significantly reducing the growth of human glioblastoma cells as a means of curing, or at least improving the survival and morbidity associated with the occurrence of glioblastoma multiforme tumors in humans. The invention is based upon the discovery that contacting glioblastoma cells with an oligomer which has a nucleoside sequence substantially complementary to FGFRlα pre-mRNA, reduces the appearance and, thus, inhibits or decreases activity of all forms of FGFR1, including FGFRlβ, and thereby suppresses the growth of the glioblastoma cells. According to a preferred aspect, the oligomers of the present invention bind to a sequence portion of RNA expressed from the human FGFR1 gene, and, according to an especially preferred aspect, the a exon, which encodes the first immunoglobulin-like domain. When brought into contact with tumor cells expressing the human FGFR1 gene, the oligomers of the present invention selectively reduce the expression or activity of at least one FGFR1 gene product, thereby suppressing the growth of the tumor cells. The invention further includes compositions of such oligomers together with a pharmaceutically acceptable carrier. According to one aspect of the present invention, a composition for inhibiting or decreasing proliferation or promoting initiation of cell death of glioma or glioblastoma cells is provided. The composition comprises an effective amount of an oligomer which is substantially complementary to and binds to FGFR1 pre- mRNA and a pharmaceutically acceptable carrier. Preferably, the oligomer has from about 10 to about 30 nucleosides, more preferably about 12 to about 30; especially preferred are oligomers of about 15 to 24 nucleosides. Preferred oligomers include phosphorothroate oligomers. Especially preferred are oligomers which have nucleoside base sequences selected from SEQ ID NO.s 1 and 15 to 19. According to another aspect, the present invention provides an oligomer which is substantially complementary to and binds to the FGFR1 pre-mRNA and more preferably to the alpha exon of the FGFR1 pre-mRNA. The oligomer preferably has from about 10 to about 30 nucleosides, more preferably from about 12 to about 30 nucleosides; especially preferred are oligomers having from about 15 to about 24 nucleosides . Preferred oligomers include phosphorothroate oligomers. Especially preferred are oligomers having nucleoside sequences selected from SEQ ID NO.s 1 and 15 to 19. According to an alternate aspect, the present invention is directed to a method of inhibiting or decreasing proliferation or promoting cell death of glioma or glioblastoma cells which comprises contracting said cells or their environment with an amount effective to inhibit or decrease cell proliferation or increase cell death of a compound which selectively inhibits or prevents activity of FGFR1 protein without substantially affecting activity of other FGFR proteins. Inhibiting or preventing activity of FGFR1 protein includes decreasing levels of FGFR1 protein in treated cells. According to an especially preferred aspect, such compounds include oligomers which are substantially complementary to FGFR1 pre-mRNA. Another feature of the invention provides vectors for transfecting human tumor cells. The claimed vectors comprise a nucleotide sequence that encodes an antisense RNA which reduces expression from the human FGFR1 gene m tumor cells, and which has the property of reducing the expression of at least one FGFR1 gene product, thereby suppressing the growth of the tumor cells. A method is provided in the invention for suppressing the growth of tumor cells. The method comprises the step of introducing the claimed antisense oligomers and compositions thereof to tumor cells expressing the FGFR1. The conditions under which the claimed method introduces the antisense molecules to the tumor cells are sufficient to reduce FGFRl gene expression in the tumor cells, and suppress the growth of the tumor cells. The above discussed and many other features and attendant advantages of the present invention will become better understood by reference to the following detailed description of the invention when taken in conjunction with the accompanying drawings. Brief Description of the Drawing Figure 1 shows the effect of antisense and control oligomers on glioblastoma cell growth in vi tro . Figure 2 shows a dose-response curve (cell number versus concentration of oligomer) for the FGFRl alpha antisense and reverse control oligomers. Figure 3 shows a time course displaying the effects of multiple treatments using antisense and control oligomers on glioblastoma cell growth. Open squares depict cell numbers/well for the non-treated control. Solid circles are cell numbers/well with a FGFRl ASα (SEQ ID No. 1) 3-day treatment. Open circles depict cell numbers/we11 with FGFRl ASα (SEQ ID NO. 1) 5 day treatment. Open triangles depict cell numbers/well with FGFRl AScont (SEQ ID NO. 10) (antisense oligonucleotide in the reverse orientation) 3-day treatment. Solid triangles depict cell numbers/well with FGFRl AScont (SEQ ID NO. 10) 5-day treatment. Figure 4 is RT-PCR Southern Blot analysis of FGFRl expression in antisense and control oligomer-treated glioblastoma cells. Panel A depicts non-treated control cells. Panel B depicts cells treated with FGFRl antisense α oligomer (SEQ ID NO. 1) . Panel C depicts cells treated with FGFRl Antisense cont oligomer (reverse orientation) (SEQ ID NO. 10) . Figure 5 is RT-PCR Southern Blot analysis of FGFR2 mRNA expression. Figure 5 depicts results in SH-SY5Y cells treated with no oligomer, FGFRlASc. oligomer [SEQ. ID. NO. 1] and FGFR2 antisense oligomer [SEQ. ID. NO. 12] . SH-SY5Y cells express FGFR2. Figure 6 shows the growth inhibitory actions of FGFR2 antisense initiation oligomers on SH-SY5Y human neuroblastoma cell growth. SYSY cells express FGFR2. Figure 7 is bFGF Western Blot analysis in FGFRl alpha antisense [SEQ. ID. NO. 1] and control [SEQ. ID. NO. 10] treated glioblastoma cells depicting the effects of these oligomers on bFGF levels. Figure 8 shows the effect of FGFRl antisense oligomers on the growth of T98 human glioblastoma cells in vi tro . Cell number was measured at day 1 (open bars) and day 7 (cross-hatched bars) . NT represents untreated controls. Figure 9 shows an RT-PCR Southern Blot of FGFRl, FGFR3, and FGFR4 demonstrating the selective reduction of FGFRl mRNA following treatment of glioblastoma cells with the FGFRlα antisense molecule (RIASc.) (SEQ ID NO. 1) compared with R control oligomers (RlαRC) (SEQ ID NO. 10) and untreated controls. GAPDH was used as a generic control . Detailed Description of the Invention According to the invention, antisense oligomers and compositions thereof are provided for inhibiting the growth of glioblastoma cells. The invention also provides vectors comprising nucleotide sequences that encode the antisense oligomers of the invention. Also included m the invention are methods for inhibiting the growth of glioblastomas in humans which involve a step of introducing the claimed antisense oligomers to human glioblastoma cells. Definitions As used herein, the term "antisense oligomer" means antisense oligonucleotides and analogs thereof and refers to a range of chemical species having a range of nucleotide base sequences that recognize polynucleotide target sequences or sequence portions through hydrogen bonding interactions with the nucleotide bases of the target sequences. The target sequences may be single- or double-stranded RNA, or single- or double-stranded DNA. The antisense oligonucleotides and analogs thereof may be RNA or DNA, or analogs of RNA or DNA, commonly referred to as antisense oligomers or antisense oligonucleotides. Such RNA or DNA analogs comprise but are not limited to 2'-0-alkyl sugar modifications, as well as methylphosphonate, phosphorothioate, phosphorodithioate, formacetal, 3' -thioformacetal, sulfone, sulfamate, and nitroxide backbone modifications, amides, and analogs wherein the base moieties have been modified. In addition, analogs of oligomers may be polymers in which the sugar moiety has been modified or replaced by another suitable moiety, resulting in polymers which include, but are not limited to, morpholino analogs and peptide nucleic acid (PNA) analogs (51) . Such analogs include various combinations of the above-mentioned modifications involving linkage groups and/or structural modifications of the sugar or base for the purpose of improving RNAseH-mediated destruction of the targeted RNA, binding affinity, nuclease resistance, and or target specificity. Antisense analogs may also be mixtures of any of the oligonucleotide analog types together or in combination with native DNA or RNA. At the same time, the oligonucleotides and analogs thereof may be used alone or in combination with one or more additional oligonucleotides or analogs thereof. The oligonucleotides may be from about 10 to about 100 nucleotides long. Although oligonucleotides of 10 to 30 nucleotides are useful n the invention, preferred oligonucleotides range from about 15 to about 24 bases in length. Antisense oligonucleotides and analogs thereof also comprise conjugates of the oligonucleotides and analogs thereof (16) . Such conjugates have properties which improve the uptake, pharmacokinetics, and nuclease resistance of the oligonucleotide, or the ability to enhance cross-linking or cleavage of the target sequence by the oligonucleotide. As used herein, the term "cell proliferation" refers to cell division. The term "growth," or "cell growth" as used herein, encompasses both increased cell numbers due to faster cell division (increased cell proliferation) and to slower rates of cell death, i.e., apoptosis or necrosis. Uncontrolled cell proliferation is a marker for a cancerous or abnormal cell type. Normal, non-cancerous cells divide regularly, at a frequency characteristic for the particular type of cell. When a cell has been transformed into a cancerous state, the cell divides and proliferates uncontrollably. Inhibition of proliferation or growth modulates the uncontrolled division of the cell. "Antisense therapy" as used herein is a generic term which includes the use of specific binding oligomers to inactivate undesirable DNA or RNA sequences in vi tro or in vivo using either triplex strand or antisense approaches. As used herein, FGFRlα exon refers either to the complete nucleotide sequence of the FGFRlof exon as set forth in [SEQ. ID. NO. 14] , or to a sequence portion of the FGFRlα exon. Sequence portions comprising the FGFRlα exon refer herein to at least a portion of the FGFRlα exon. FGFR Gene Expression As used herein, "FGFR gene expression" refers to RNA expression from a human FGFR gene, or to FGFR protein production from a human FGFR gene. Four structurally related genes encoding high affinity FGF receptors (FGFR) have been identified (4-8) . In addition to high-affinity binding sites, cells exhibit low-affinity FGF binding sites (17) which have been characterized as either cell-associated or extra- cellular heparan sulfate proteoglycans (18,19) . Binding to the low-affinity, glycosaminoglycan sites appears to be obligatory for FGF binding to high affinity receptors and for biological activity (20,21) . Cells deficient in heparan sulfate biosynthesis are not able to bind or respond to bFGF (31-32) . However, the addition of either free heparan or heparan sulfate restores high- affinity binding of bFGF (20) . These results demonstrate that heparin-like, low-affinity sites play an important role in the regulation of bFGF activity and in the response of cells to bFGF. FGFR Gene Structures Structural features common to members of the FGFR family include a signal peptide, two or three immunoglobulin-like loops in the extracellular domain, a hydrophobic transmembrane domain and a highly conserved tyrosine kinase domain split by a short kinase insert sequence (22) . Overall, the proteins encoded by the four FGFR genes are strikingly similar. The most closely related proteins are FGFRl and FGFR2 (72% amino acid identity) , whereas FGFRl and FGFR4 are the least closely related (55% identity) . Each of the FGFR' s can bind several different types of FGF'S. However, there are several reports of cell- and tissue-specific expression of FGF receptors and responsiveness to different FGF family members (23,24,25) . One mechanism for generating this selective responsiveness to different FGF family members would be to alter the ligand binding specificity or affinity through alternative splicing of RNA, thereby producing several receptor isoforms from a single gene. FGFR Structural Variants Structural variants of FGFRl, FGFR2 and FGFR3 are, in fact, generated by alternative splicing of their RNA transcripts (22) . The divergent receptors generated by this process manifest different ligand-binding specificities and affinities (22) . One common structural variation that involves the second half of the third immunoglobulin (Ig)-like disulfide loop of FGFRl and FGFR2 dramatically alters these receptors' ligand-binding properties (26) . Another splicing variant results in FGFRs containing either two or three Ig-like domains in the extracellular region (5,27,28) . Alternative RNA splicing involving both the first and third Ig-like domains is subject to cell- and tissue-specific processing that reflect the changing FGF requirement that occurs during tissue growth and differentiation (5,24) The FGFR's appear to be differentially expressed in diverse tissue types and during different periods of development. Studies that have examined the distribution of FGFR's have relied principally on Northern blotting, the RNase protection assay and in si tu hybridization to demonstrate the presence of mRNA transcripts. In general, FGFRl and FGFR2 appear to be broadly distributed, while FGFR3 and FGFR4 exhibit more restricted patterns of distribution. For example, in the developing embryo FGFRl transcripts are predominant in the central nervous system and in mesenchyme . FGFR2 transcripts are also observed in the central nervous system and in epithelium (25) . FGFR3 transcripts are predominantly expressed in the central nervous system and cartilaginous rudiments of developing bone. In contrast to the other FGFR's, which are expressed to some degree in the central nervous system, FGFR4 transcripts are observed in developing endoderm, the myotomal compartment of somites and in myotomally-- derived skeletal muscle. The unique temporal and spatial patterns of expression exhibited by different FGFR family members strongly suggest that they have distinct, but still unknown roles in tissue development, maintenance and pathology. FGFR Expression and Trans ormation In some types of human cancers, FGFR family members are amplified (31) . Recent reports demonstrate a change in the expression of FGFRs during the course of a normal human tissue progressing to a malignant one (32,33) . These reports demonstrate that in human glioblastomas differential expression and alternative splicing of FGFRs play a role in the transformation of normal cells and in malignant progression of astrocytic tumors. Normal astrocytes express the FGFR2 receptor and do not express the FGFRl receptor. At the earliest stages of transformation, astrocytes begin to express FGFRl. Also at the earliest stage of transformation, FGFRl is expressed in both the alpha and beta isoforms, although the alpha form generally predominates. As astrocytic tumors progress to the more malignant stages eventually culminating in a glioblastoma multiforme, their expression of FGFRl shifts from the alpha form to almost exclusively the beta form. In addition to shifting to the beta form of FGFRl, the cells stop expressing FGFR2. Preferred Antisense Oligomers The present invention is based upon the finding that antisense oligomers substantially complementary to and binding at least a portion of the FGFRl pre-mRNA and, more preferably, the alpha exon of the FGFRl pre- mRNA or mRNA inhibited or reduced expression of all FGFRl isoforms and resulted in growth suppression of glioblastoma cells. In particular, according to the present invention it was demonstrated that upon introducing antisense oligomers of the present invention to glioblastoma tumor cells, the growth of the tumor cells was suppressed, and that FGFRl mRNA was selectively suppressed upon application of these antisense molecules, as well as suppressing the expression of FGFRlo? protein, and that further, FGFRlβ, which is a major alternatively spliced form of FGFRl, was suppressed. According to an aspect of the present invention, it was demonstrated that FGFRl antisense oligomers complementary to the alpha exon were effective in reducing cell proliferation and reducing expression of FGFRl mRNA. The present invention takes advantage of using antisense oligomers substantially complementary to and binding to at least a portion of the FGFRl pre-mRNA, more preferably alpha exon pre-mRNA, to suppress glioblastoma cells in which the major pre-mRNA or mRNA transcript encodes the beta isoform of FGFRl protein. Nevertheless, FGFRl-alpha exon specific antisense oligonucleotide proved more effective in suppressing glioblastoma cell growth than the oligonucleotide complementary to the FGFRl beta exon or complementary to the initiation site, although antisense oligomers directed to the translation initiation site proved effective in suppressing the growth of glioblastoma cells. Antisense oligomers suitable for use in the invention include nucleotide oligomers which are preferably from about 10 to about 30 bases long, more preferably 12 to about 30 bases long, and most preferably 15 to 24 bases long. The oligonucleotides are preferably selected from those oligonucleotides substantially complementary to at least a portion of the FGFRl alpha-exon or the translation start site. "Substantially complementary" as used herein means an antisense oligomers having about 80% homology with an antisense oligonucleotide which itself is complementary to and specifically binds to at least a sequence portion of the human FGFRl alpha exon pre-mRNA. While not wishing to be bound by a mechanism of action, it is believed that degrading pre-mRNA or mature mRNA, at a site such as at the alpha-exon or at the translation start site, prevents formation of a functional transcript, thereby blocking formation of the protein. It should also be appreciated that antisense oligomers suitable for use in the invention may also include oligonucleotides which are directed to and substantially complementary to target sequences or sequence portions flanking either the alpha exon site or translation initiation site along the FGFRl mRNA. The flanking sequence portions are preferably from about two to about twenty bases in length. It is also preferable that the antisense oligomers be substantially complementary to a sequence portion of the pre-mRNA or mRNA that is not commonly found in pre-mRNA or mRNA of other genes to minimize homology of antisense oligomers for pre-mRNA or mRNA coding strands from other genes. According to an especially preferred aspect the invention comprises an antisense or complementary oligomer comprising one of the following sequences [SEQ. ID. NO. 1 and 15 to 19] 5' -CTGCACATCGTCCCGCAGCC-3' [SEQ. ID. NO. 1] 5' -GCACATCGTCCCGCAGCC-3' [SEQ. ID. NC. 15] 5' -ACATCGTCCCGCAGCC-3' [SEQ. ID. NO. 16] 5' -CGTCCCGCAGCC-3' [SEQ. ID. NO. 17] 5' -GCACATCGTCCCGCAGCCGA-3' [SEQ. ID. NO. 18] 5' -CTGCACATCGTCCCGC-3' [SEQ. ID. NO. 19] Preferred antisense oligomers include phosphorothioate oligomers. We have found that all- phosphorothioate oligomers, especially those having sequences selected from SEQ. ID. NOS. 1 and 15 and 19 to be especially preferred. Particularly preferred are oligomers of SEQ. ID. NOS. 1 and 18. We have found that all phosphorothioate oligomers of different synthesis lots may vary in their activity for decreasing tumor cell growth. Accordingly, it is preferred to prescreen such oligomer lots for activity in order to select those lots having high activity using a suitable screening assay in order to select high activity lots for treating cells or tumors. A suitable screening assay for screening of oligomer activity is set forth in Example 9. As set forth in the Examples below, the antisense oligomer of SEQ. ID. NO. 1 is substantially complementary to nucleotides numbered 284 to 303 in the FGFRl gene sequence shown in SEQ. ID. NO. 14. The FGFRl alpha exon is 267 nucleotides long, and stretches from nucleotide number 210 to number 467 of SEQ. ID. NO. 14. These antisense oligomers when brought into contact with tumor cells expressing FGFRl gene products (pre-mRNA and FGFRl protein) , reduce the expression of at least on FGFRl gene product and inhibit the growth of those cells . It will be appreciated by those skilled in the art to which this invention pertains that antisense oligomers having a greater or lesser number of substituent nucleotides, or that extend further along the FGFRl pre-mRNA or mRNA in either the 3' or 5' direction than the preferred embodiments, or which comprise a sequence which is substantially complementary to and specifically binds to at least a portion of the targeted FGFRl alpha exon but which also inhibit cell proliferation are also within the scope of the inventio . The term "oligomer" or "oligonucleoside" refers to a chain of nucleosides which are linked by internucleoside linkages which is generally from about 4 to about 100 nucleosides in length, but which may be greater than about 100 nucleosides in length. They are usually synthesized from nucleoside monomers, but may also be obtained by enzymatic means. Thus, the term "oligomer" refers to a chain of oligonucleosides which have internucleosidyl linkages, linking nucleoside monomers and, thus, include deoxy- and ribo- oligonucleotides, nonionic oligonucleoside alkyl- and aryl-phosphonate analogs, alkyl- and aryl-phosphonothioates, phosphorothioate or phosphorodithioate analogs of oligonucleotides, phosphoramidate analogs of oligonucleotides, neutral phosphate ester oligonucleoside analogs, such as phosphotriesters and other oligonucleoside analogs and modified oligonucleosides, and also nucleoside/non-nucleoside polymers. The term also includes nucleoside/non-nucleoside polymers wherein one or more of the phosphorus group linkages between monomeric units has been replaced by a non-phosphorous linkage such as a formacetal linkage, a thioformacetal linkage, a morpholino linkage, a sulfamate linkage, a silyl linkage, a carbamate linkage, an amide linkage, a guanidine linkage, a nitroxide linkage, or a substituted hydrazine linkage. These analogs may be additionally modified to contain 2'0-alkyl substitutions to alter binding affinity with DNA and RNA targets. It also includes nucleoside/non-nucleoside polymers wherein both the sugar and the phosphorous moiety have been replaced or modified such as morpholino base analogs, or polyamide base analogs. It also includes nucleoside/non-nucleoside polymers wherein the base, the sugar, and the phosphate backbone of the non-nucleoside are either replaced by non-nucleoside moiety or wherein a non-nucleoside moiety is inserted into the nucleoside/non-nucleoside polymer, optionally, said non-nucleoside moiety may serve to link other small molecules which may interact with target sequences or alter uptake into target cells. It is preferable to use chemically modified derivatives (i.e. derivatized oligomers) or analogs of antisense oligomers in the performance of the invention rather than "native" or unmodified oligodeoxynucleotides. "Native" oligodeoxynucleotides can be conveniently synthesized with a DNA synthesizer using standard phosphoramidite chemistry. Suitable derivatives, and methods for preparing the derivatives, involve alterations that (1) increase the oligomer' s resistance to nuclease, for example, methylphosphonate (35) , alphadeoxynucleotides (36) , and 2'-0-methyl- ribonucleosides (37) ; (2) increase the affinity of the oligomer to the target, for example, covalently-linked derivatives such as acridine (38) ; and (3) increase the cleavage ratio, for example, Fe-ethylenediamine tetraacetic acid (EDTA) and analogues (43) , 5- glycylamido-1, 10-o-phenanthroline (44) , and diethylenetriaamine-pentaacetic acid (DTPA) derivatives (45) . Other suitable derivatives include, but are not restricted to, phosphorothioate and dithioate (34) , alkylated oligomers (e.g., N-2-chlorocethylamine) 4 4 (39,40) , phenazine (41), 5-methyl-N -N -ethanocytosine (42) , and various chimeric oligonucleosides comprised of the above-stated modifications and derivatives. All of the above publications are hereby specifically incorporated by reference as if fully set forth herein. Analogs of the present invention include combinations of the above-mentioned modifications involving linkage groups and/or structural modifications of the sugar or base for the purpose of improving RNAseH- mediated destruction of the targeted RNA, binding affinity, nuclease resistance, and or target specificity. Thus, it will be seen that the present invention provides synthetic oligomers having one or more segments including mixed internucieosidyl linkages, particularly oligomers having chirally pure or enriched phosphonate internucleosidyl linkages interspersed with single non- phosphonate internucleosidyl linkages and methods for their preparation. Such phosphonate internucleosidyl linkages include lower alkylphosphonate internucleosidyl linkages of 1 to 3 carbon atoms and lower alkylphosphonothioate (alkylthiophosphonate) internucleosidyl linkages of 1 to 3 carbon atoms. These mixed oligomer segments preferably have phosphonate internucleosidyl linkages interspersed between single non-phosphonate internucleosidyl linkages in a ratio of from 1 to about 1 to 1 to about 4 non-phosphonate linkages to phosphonate linkages. According to a preferred aspect, such oligomers have alternating chirally pure phosphonate internucleosidyl linkages which alternate with non-phosphonate internucleosidyl linkages. Oligomers comprising such segments, particularly in one or more non-RHaseH-activating regions, may be used to prevent or interfere with expression or translation of a single-stranded RNA target sequence. The chimeric oligonucleosides have an overall nucleoside base sequence, including the RHaseH-activating and non-RHaseH- activatmg regions, which is sufficiently complementary to the RNA target sequence to hybridize therewith. Preferred chirally pure phosphonate linkages include R p lower alkylphosphonate linkages, and more preferred are R p methylphosphonate internucleosidyl linkages. Preferred non-phosphonate linkages include phosphodiester, phosphorothioate and phosphorodithioate. According to an especially preferred aspect, R p -enriched oligomers are provided having chirally pure R p -methyl phosphonate linkages which alternate with phosphodiester linkages in the non-RHaseH-activating region of the compound. These alternating oligomers have been found to exhibit enhanced binding affinity for an RNA target sequence and also increased nuclease resistance and specificity. Tne present invention likewise includes chimeric antisense oligomers having enhanced potency as antisense inhibitors of gene expression comprising one or more segments with methylphosphonate internucleosidyl linkages enhanced for the R p configuration which are interspersed between non-phosphonate internucleosidyl linkages, preferably phosphodiester or alternatively phosphorothioate or phosphorodithioate linkages. Chimeric oligomers of the invention, or segments thereof, having a predetermined base sequence of nucleosidyl units and having chirally pure phosphonate internucleosidyl linkages mixed with non-phosphonate linkages wherein the phosphonate linkages are interspersed between single non-phosphonate linkages may be prepared by coupling to one another individual nucleoside dimers, trimers or tetrameres of preselected nucleoside base sequence having chirally pure or racemic phosphonate or other internucleosidyl linkages. The chirally-selected methylphosphonate and other monomers, dimers, trimers and the like can be coupled together by a variety of different methods leading to the following, non-exclusive, types of internucleosidyl linkages: phosphodiester, phosphotriester phosphorothioate, phosphorodithioate, phosphoramidate, phosphorofluoridates, boranophosphates, formacetal, and silyl . Utility and Administration Derivatized oligomers may be used to bind with and then irreversibly modify a target site in a nucleic acid by cross-linking (psoralens) or cleaving (EDTA) . By careful selection of a target site for cleavage, one of the strands may be used as a molecular scissors to specifically cleave a selected nucleic acid sequence. The oligomers provided herein may be derivatized to incorporate a nucleic acid reacting or modifying group which can be caused to react with a nucleic acid segment or a target sequence thereof to irreversibly modify, degrade or destroy the nucleic acid and thus irreversibly inhibit its functions. These oligomers may be used to inactivate or inhibit or alter expression of a particular gene or target sequence of the same in a living cell, allowing selective inactivation or inhibition or alteration of expression. The target sequence may be RNA, such as a pre-mRNA or an mRNA. mRNA target sequences include an initiation codon region, a coding region, a polyadenylation region, an mRNA cap site or a splice junction. Since the oligomers provided herein may form duplexes or triple helix complexes or other forms of stable association with transcribed regions of nucleic acids, these complexes are useful in antisense therapy. Many diseases and other conditions are characterized by the presence of undesired DNA or RNA, which may be in certain instances single stranded and in other instances double stranded. These diseases and conditions can be treated using the principles of antisense therapy as is generally understood in the art. Antisense therapy includes targeting a specific DNA or RNA target sequence through complementarity or through any other specific binding means, in the case of the present invention by formation of duplexes or triple helix complexes. According to one aspect of the present invention, these antisense oligomers have a sequence which is complementary to a portion of the RNA transcribed from the selected target gene . Although the exact molecular mechanism of inhibition has not been conclusively determined, the duplexes so formed may inhibit translation, processing or transport of an mRNA sequence. According to an alternate aspect of the present invention, interference with or prevention of expression, or translation of a selected RNA target sequence may be accomplished by triple helix formation using oligomers of the present invention as a triplex oligomer pair having sequences selected such that the oligomers are complementary to and form a triple helix complex with the RNA target sequence and thereby interfere with or prevent expression of the targeted nucleic acid sequence. Such triple strand formation can occur in one of several ways . Basically, two separate or connected oligomers may form a triple strand with the single stranded RNA. Accordingly, the antisense oligomers (including triplex oligomer pairs) of the present invention find use in preventing or interfering with the expression of a target sequence of double or single stranded nucleic acid functionally equivalent to the human FGFRl gene by formation of triple helix complexes to achieve down regulation of the target FGFRl gene thereby suppressing the growth of tumor cells. As a general matter, the oligomers employed will have a sequence that is complementary to the sequence of the target nucleic acid. However, absolute complementarity may not be required; in general, any oligomer having sufficient complementarity to form a stable duplex (or triple helix complex as the case may be) with the target nucleic acid is considered to be suitable. Since stable duplex formation depends on the sequence and length of the hybridizing oligomer and the degree of complementarity between the antisense oligomer and the target sequence, the system can tolerate less fidelity (complementarity) when longer oligomers are used. This is also true with oligomers which form triple helix complexes. However, oligomers of about 8 to about 40 nucleosidyl units in length which have sufficient complementarity to form a duplex or triple helix structure having a melting temperature of greater than about 40°C under physiological conditions are particularly suitable for use according to the methods of the present invention. The oligomers for use in the instant invention may be administered singly, or combinations of oligomers may be administered for adjacent or distant targets or for combined effects of antisense mechanisms with the foregoing general mechanisms. In therapeutic applications, the oligomers can be formulated for a variety of modes of administration, including oral, topical or localized administration. It may be beneficial to have pharmaceutical formulations containing acid resistant oligomers that may come in contact with acid conditions during their manufacture or when such formulations may themselves be made acidic, to some extent, in order to be more compatible with the conditions prevailing at the site of application. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition. The oligomer active ingredient is generally combined with a carrier such as a diluent of excipient which may include fillers, extenders, binding, wetting agents, disintegrants, surface-active agents, erodible polymers or lubricants, depending on the nature of the mode of administration and dosage forms. Typical dosage forms include tablets, powders, liquid preparations including suspensions, emulsions and solutions, granules, and capsules. Certain of the oligomers of the present invention may be particularly suited for oral administration which may require exposure of the drug to acidic conditions in the stomach for up to about 4 hours under conventional drug delivery conditions and for up to about 12 hours when delivered in a sustained release form. For treatment of certain conditions it may be advantageous to formulate these oligomers in a sustained release form. U.S. Patent No. 4,839,177 to Colombo et al . , and U.S. Patent No. 5,422,123 to Conte et al . , the disclosures of which are incorporated herein by reference, describe certain preferred controlled-rate release systems. For oral administration, these oligomers may preferably have 2'-0-alkyl, more preferably 2' -0-methyl , nucleosidyl units; these oligomers are formulated into conventional as well as delayed release oral administration forms such as capsules, tablets, and liquids. Systemic administration of the claimed oligomers can be achieved by transmucosal or transdermal means, or the compounds can be administered orally. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, detergents may be used to facilitate permeation. Transmucosal administration may be through use of nasal sprays, for example, as well as formulations suitable for administration by inhalation, or suppositories. The antisense oligomers of the present invention can also be combined with a pharmaceutically acceptable carrier for administration to a subject. Examples of suitable pharmaceutical carriers are a variety of cationic lipids, including, but not limited to N- (1-2,3- dioleyloxy)propyl) -n,n,n-trimethylammonium chloride (DOTMA) and dioleoylphophotidylethanolamine (DOPE) . Preferred cationic lipids inlcude those described in U.S. patent applications, Serial No. 08/484,716 filed June 7, 1995, Serial No. 08/483,465 filed June 7, 1995 and Serial No. 08/505,802 filed July 21, 1995, the disclosures of which are incorporated herein by reference. Liposomes are also suitable carriers for the antisense oligomers of the invention. Another suitable carrier is a slow-release gel or polymer comprising the claimed antisense molecules (92,93) . The antisense oligomers may be administered to patients by any effective route, including intravenous, intramuscular, intrathecal, intranasal, intraperitoneal, intratumoral, subcutaneous injection, in εi cu injection and oral administration. Oral administration may require enteric coatings to protect the claimed antisense molecules and analogs thereof from degradation along the gastrointestinal tract. The antisense oligomers may be mixed with an amount of a physiologically acceptable carrier or diluent, such as a saline solution or other suitable liquid. The antisense oligomers may also be combined with other carrier means to protect the antisense molecules or analogs thereof from degradation until they reach their targets and/or facilitate movement of the antisense molecules or analogs thereof across tissue barriers. The present invention includes a method for suppressing the growth of tumor cells, including glioblastoma cells. The method involves the step of introducing the claimed antisense oligomer to the tumor cells which express the FGFRl gene under conditions sufficient to reduce FGFRl gene expression in the tumor cells. In an alternative embodiment of the claimed method, the step of introducing involves local delivery to brain tissue, which involves the step of surgically resecting the tumor, i.e. surgically removing as much of the tumor mass as feasible. A subsequent step involves localized introduction of the claimed antisense molecules to the cells of the tumor mass remaining at the site of resection. Localized introduction of the claimed antisense molecules to the tumor cells may involve placing slow release polymers comprising the claimed antisense molecules at the site of resection. The slow release polymers comprise a sufficient amount of the antisense molecules to inhibit the growth of the tumor cells. Methods for local delivery of compounds and compositions thereof to the brain are well known in the art (48,49) . Other methods of local delivery involve stereotactic administration of intratumoral chemotherapy (50,51) . The antisense oligomers are administered in amounts effective to inhibit cancer or neoplastic cell growth, and in particular, glioblastoma cell growth in si tu . The actual amount of any particular antisense oligomer administered will depend on factors such as the type and stage of cancer, the toxicity of the antisense oligomer to other cells of the body, its rate of uptake by cancer cells, and the weight and age of the individual to whom the antisense oligomer is administered. An effective dosage for the patient can be ascertained by conventional methods such as incrementally increasing the dosage of the antisense oligomer from an amount ineffective to inhibit cell proliferation to an effective amount. It is expected that concentrations presented to cancer cells, and in particular, glioblastoma cells, in the range of about 10 nM to about 30 μM will be effective to inhibit cell proliferation. Methods for determining pharmaceutical/pharmacokinetic parameters in chemotherapeutic applications of antisense oligonucleotides for treatment of cancer or other indications are known in the art (52) . The antisense oligomers are administered to the patient for at least a time sufficient to inhibit proliferation of the cancer cells. The antisense oligomers are preferably administered to patients at a frequency sufficient to maintain the level of antisense oligomers at an effective level in or around the cancer cells. To maintain an effective level, it may be necessary to administer the antisense oligomers several times a day, daily or at less frequent intervals. Antisense oligomers are administered until cancer cells can no longer be detected, or have been reduced in number such that further treatment provides no significant reduction in number, or the cells have been reduced to a number manageable by surgery or other treatments . The length of time that the antisense oligomers are administered will depend on factors such as the rate of uptake of the particular oligomer by cancer cells and time needed for the cells to respond to the oligomer. The antisense oligomers of the invention may be administered according to the claimed method to patients as a combination of two or more different antisense oligomer/oligodeoxynucleotide sequences or as a single type of sequence. Accordingly, the claimed antisense oligomer, compositions thereof and methods of use include compositions of one or more claimed antisense oligomers, each having the claimed property of reducing the expression of at least one FGFRl gene product and thereby suppressing the growth of tumor cells, the antisense oligomers mixed together and added simultaneously by the local delivery system. The present invention further comprises vectors for transfecting human tumor cells. The claimed vector comprises a nucleotide sequence that encodes an antisense RNA which reduces the expression from the human FGFRl gene. The antisense RNA expressed from the vector- delivered nucleotide sequence binds with a sequence portion of RNA expressed from the FGFRl gene. The antisense RNA reduces the expression of at least one FGFRl gene product, thereby suppressing the growth of the tumor cells. A preferred form of the antisense RNA is substantially complementary to and binds specifically to the FGFRl alpha exon. The present invention further involves a method using the claimed vector for suppressing the growth of tumor cells by introducing to tumor cells which express the FGFRl gene the claimed antisense oligonucleotide as an RNA. The method comprises the step of transfecting the tumor with the claimed vector which comprises a sequence that encodes an antisense RNA which is substantially complementary to and binds the FGFRl gene. A further step involves the expression of the sequence encoding the antisense RNA, which thereby results in reduction of FGFRl gene expression in the tumor cells, and suppression of their growth. Vectors for transfecting/transforming mammalian cells, which vectors comprise nucleotide sequences coding for antisense RNA that inhibit the expression of target genes are well known in the art (57) . Techniques for constructing such vectors and methods of using such vectors for transforming mammalian cancer cells to suppress tumorigenicity through down regulation of oncogenes, protooncogenes, and other endogenous genes (e.g. FGFRl) have been widely reported (57) . Protocols are also known for introducing an antisense RNA to tumor cells by transfecting tumor cells with a vector comprising a sequence that encodes an antisense RNA which is specific for and binds RNA expressed from a chosen target gene or RNA expressed from a chosen target locus comprising a specific sequence portion (57) . The growth inhibitory actions and the specificity of the claimed FGFRl-alpha exon-specific antisense oligomers demonstrated in the Examples below. Examples General Methods The Examples below use the following protocols: A. Cells and Cell Cultures. The human cells used in these examples were SNB-19 and T98 cell lines, which were derived from high grade glioblastomas after culturing small fragments of tumor biopsies. Cell line T98 has been deposited in the American Type Culture Collection, and designated as ATCC CRL 1690. SNB-19 cells are described in Gross et al . (53) . The derivation of these tumors was confirmed by histological analysis, as described in Gross et al . (53) . The glioma cell lines, which were mycoplasma free, were maintained as described in Gross et al. (53) . Cell line SH-SY5Y is a neuroblastoma cell line and has been described in, inter alia , Gray et al . (58) , Patterson, et al . (59) , and Patterson et al . (60) . B. Cell Growth and Dose Response. Glioma cells were 5 2 plated at 1 x 10 cells/8.0 cm tissue culture well in serum supplemented medium (10%) . Within 18-20 hours postplating, the serum-supplemented medium was removed and the cells were washed three times with phosphate- buffered saline (PBS) and converted to serum free medium (SFM) . Antisense oligomers, including FGFRlα antisense oligomers, or the appropriate control oligonucleotides were solubilized in sterile water and added at a final concentration of 30 micromolar directly to the cells at the time of conversion to SFM. This was considered as day 1. The cells were treated for three consecutive days with antisense oligonucleotides. In the time course study (Figure 3, Examples 2 and 3) , one set of cells was additionally treated on days 7 and 8 with antisense or control oligonucleotides. One to eleven days later the cells were washed twice with PBS and removed from the tissue culture wells by trypsinization (0.25%) in PBS. Cell number was determined using a hemocytometer. After being counted, cells were pelleted and used for mRNA purification and PCR analysis. C. RNA-PCR Analysis. Relative levels of expression of FGFRl a and FGFRlβ transcripts in cell lines were determined by RNA-PCR analysis. Poly A [plus] mRNA was extracted using the MicroFast Tract kit as per instructions of the manufacturer (Invitrogen, San Diego, CA) . For tumor and adjacent brain, RNA was extracted from 20 frozen sections (4 microns) . First-strand DNA synthesis was performed using a cDNA cycle kit (Invitrogen) and random primers. For analysis of human FGFRl, nucleotide primers Pla (SEQ. ID. NO. 2) , corresponding to nucleotides -67 to -44 at the 5' end, and Plb (SEQ. ID. NO. 3), complementary to nucleotides 1014-1035 at the 3' end of the mRNA for FGFRl (55) . For analysis of human FGFR2, nucleotide primers Pla- R2 (SEQ. ID. NO. 4) (5' -AAGTGTGCAGATGGGATTAACGTC-3' ) , corresponding to nucleotides 113-136 at the 5' end and Plb-R2 (SEQ. ID. NO. 5) (5' -ATTACCCGCCAAGCACGTATAT-3 ' ) complementary to 1196-1217 at the 3' end of the mRNA for FGFR2 were used. PCR was generally performed for 3 cycles at 96 for o o 30 seconds, 64 for 15 seconds, and 72 for 60 seconds with a Perkin Elmer Cetus Gene Amp PCR system 9600. As a control for mRNA loading, GAPDH (glyceraldehyde 3- phosphate dehydrogenase) cDNA was amplified using nucleotide primers corresponding to nucleotides 27-46 at the 5' end (5'ACGGATTTGGTCGTATTGGG-3 ' ) (SEQ. ID. NO. 6) and complementary to nucleotides 238-257 (5'- TGATTTTGGAGGGATCTCGC-3' ) (SEQ. ID. NO. 7) at the 3' end of mRNA for GAPDH (56) . Conditions were the same as those used for FGFRl. The GAPDH amplification product 32 was radiolableled with P-dCTP during the final two PCR cycles (32 total cycles) , run on a 6% polyacrylamide gel and exposed to x-ray film. Reaction mixtures (25 microliters) contained 10 mM Tris-HCl (pH 8.3) , 1.5 mM MgCl , 50 mM KCl, 0.1 mg/ml gelatin, 0.8 units of Taq polymerase (Perkin Elmer-Cetus) , 0.20 mM dNTPs and 0.5 micromolar of each primer. Relative levels of FGFRlα and FGFRlβ transcripts were determined by PCR-Southern blot analysis. PCR products were separated on 1.5% agarose gels and transferred to nylon membrane filters (Hybond-N, 32 Amersham) . The filters were hybridized to a P-labeled FGFRl oligonucleotide complementary to nucleotides 610- 630 (55) which is derived from a sequence common to alpha, beta, and gamma isoforms (5'ATAACGGACCTTGTAGCCTCC- 3') (SEQ. ID. NO. 8) and internal to PCR primers Pla and Plb. FGFR2 amplification was monitored using an oligonucleotide corresponding to nucleotides 192-212 (5'- GGTCGTTTCATCTGCCTGGTC-3' ) (SEQ. ID. NO. 9) (Dionne et al . , 1990b) . FGFRl and FGFR2-specific oligonucleotides only hybridized with their respective amplification product. Signal intensity was measured directly from the hybridized nylon membrane using a Phosphorlmager (Molecular Dynamics) . PCR amplification was evaluated through a range of 20 to 40 cycles. Accumulation of PCR amplification products was linear through 35 cycles as previously described (32) . FGFRlβ/FGFRlα ratios were constant over the linear range of amplification. All PCR-Southern blots were performed a minimum of three times for every sample. D. Preparation of Cell Extracts. Cultured cells were homogenized in a buffer of 10 mM Tris-HClpH 7.0, 2M NaCl and 0.1% CHAPS (3-3-cholamidopropyl-dimethylammonio- 1-propanesulfonate) detergent containing the protease inhibitors leupeptin, 10 micrograms/ml, 0.2 mM PMSF (phenylmethylsulfonylfluoride) , and 100 micrograms/ml of pepstatin, bestatin and aprotinin (Boehringer Mannheim) . The homogenate was centrifuged at 14,000 x g for 30 minutes. The supernatant was removed and stored at -80 C. Aliquots were taken for protein determinations using the Bio-Rad protein detection systems (Hercules, CA) . Supernatants were either analyzed directly by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS- PAGE) or first incubated with Heparin-Affigel (Bio-Rad) to concentrate heparin-binding proteins. Extracts to be enriched for heparin binding proteins were diluted 1:5 in PBS and incubated overnight with 50 o microliters of Heparin-Affigel at 4 C. This volume of Heparin-Affigel binds at least 1 microgram of purified human recombinant bFGF (hr-bFGF, Synergen, Boulder, CO) . Heparin-Affigel was then centrifuged at 14,000 x g for 10 minutes and the supernatant was removed. The Heparin- Affigel was rinsed three times in PBS and proteins were eluted by boiling for 5 minutes in sample buffer containing 5% 2-mercaptoethanol and 2.5% SDS. E. Gel Electrophoresis and Western Blot Analysis. Heparin-binding proteins were resolved by SDS-PAGE using a 15% gel and transferred to nitrocellulose. Nonspecific sites were blocked by incubating nitrocellulose in TBST (10 mM Tris-HCl pH 8.0, 150 mM NaCl, 0.05% Tween 20) containing 5% powdered milk. Blots were either stained with Poncau red or incubated overnight with the anti-bFGF monoclonal antibody, DE6 at a 1:1000 dilution. In control experiments, blots were incubated in TBST in the absence of primary antibody or with protein A purified mouse IgG. Blots were washed three times for 10 minutes each in TBST and subsequently incubated with a biotin- conjugated goat anti-mouse secondary antibody (Amersham) (1:500) for 45 minutes at room temperature. The blots were washed three times for 10 minutes each in TBST and subsequently incubated with a streptavidin (1:1000)- biotinylated horseradish peroxidate (1:2500) complex in TBST for 45 minutes at room temperature. The blots were then washed four times for 10 minutes each in TBST. 6/21471 PCIYUS96/00331 31 Immunoreactive bands were visualized by developing the blot with Amersham ECL reagents according to the manufacturer's specifications. Following a one-minute exposure to the ECL reagents, the blots were covered with Saran Wrap and exposed to x-ray film for 10-12 minutes. The molecular weights of bFGF proteins were determined by comparison with biotinylated markers (Bio-Rad) and a human recombinant bFGF standard (Synergen, Boulder, CO) . Example 1 Preparation of Antisense Oligomers Synthesis of phosphorothioate oligonucleotides in a 3' to 5' direction was achieved on a solid support. A dimethoxytritryl (DMT) protected starting nucleoside attached to solid support such as controlled pore glass was placed in a reaction vessel (300 μmoles) . The DMT protecting group is removed with deblock (2.5% v/v dichloroacetic acid in dichloromethane, 30 eq) with repeated treatment (4-7 times depending on the base) to insure complete removal of the protecting group. The support was washed with acetonitrile to remove excess acid from the support. The desired β-cyanoethyl phosphoramidite nucleoside (2 eq. with respect to starting nucleoside on support) was mixed with ethylthiotetrazole (6 eq) under argon stirring for 5 minutes. The excess monomer and activator were washed off the support with acetonitrile. The phosphite intermediate was sulfurized for 10 minutes with 3H-1,2- benzodithiole-3-one 1,1 dioxide (Beaucage reagent, 5 eq.) . Cap A (40% acetic anhydride in THF) and Cap B (0.625% DMAP in pyridine were mixed and used to cap off excess alcohols that were not coupled to the amidite monomer. The whole cycle was then repeated until the desired length oligomer had been synthesized. The final DMT was removed with deblock as described above. The support was then placed in a pressure vessel and the oligomer was removed from the support and the base labile protecting groups on the heterocyclic amines removed with concentrated ammonium hydroxide. The solid support was filtered away from the ammonium hydroxide solution and the ammonia removed in vacuo . The residue was taken up in the mobile phase for the purification and the oligonucleotides purified by ion-exchange chromatography to give material that was >97% pure. The usual yields were around 1.5 mg/μmole of starting material . Example 2 Effect of Claimed Antisense Oligomer on Glioblastoma Cell Growth Using the general methods described above, the effects of FGFRlα-exon specific antisense oligomers on growth of human glioblastoma cells were examined. The following phosphorothioate oligomers, synthesized as described above in Example 1, were introduced at concentrations of 30 μM to glioblastoma cells: O R2AS lnι [SEQ. ID. NO. 12] is FGFR2- initiation site exon-specific antisense oligonucleotide. o RlAS e [SEQ. ID. No. 11] is FGFR13 exon specific antisense oligonucleotide. o R1AS 0 [SEQ. ID. NO. 1] is FGFRlα exon specific antisense oligonucleotide. o RlAS lnι [SEQ. ID. NO. 13] is FGFRl- initiation site exon specific antisense oligonucleotide o RlAS cont [SEQ. ID. NO. 10] is FGFRlα-exon specific antisense oligonucleotide in the reverse orientation As shown in Figures 1, 2 and 3, the introduction of FGFRlof-exon-specific antisense oligonucleotide (RlASα) to human glioblastoma cells at a concentration of 30 μM resulted in a consistent and highly reproducible 70-80% reduction in cell density. The effect was saturable and dose-dependent . This finding indicates the effectiveness of antisense oligomer which specifically binds to at least a portion of pre-mRNA or RNA, or at least a portion of the alpha exon pre-mRNA or RNA, expressed from the human FGFRl gene for suppressing the growth of tumor cells, and, in particular, glioblastoma cells. In Figure 1, the bar designated "Cont" stands for control cells, which were not treated with oligomer. Example 3 Effects of Control Oligomers on Glioblastoma Cell Growth Using the general methods described above, the effects of control phosphorothioate antisense oligomers on growth of human glioblastoma cells were examined. The addition of the following phosphorothioates oligomers used as controls had no significant effect on glioblastoma cell density in culture when used at equal or greater concentrations than the effective antisense oligomer of the invention: (a) FGFRlα-exon specific antisense oligonucleotide in the reverse orientation (RlAS cont ) [SEQ. ID. NO. 10] ; (b) FGFR2-initiation site exon-specific antisense oligonucleotide (R2ASini) [SEQ. ID. NO. 12] . The effect of FGFRlβ specific antisense oligonucleotide (RIASβ) [SEQ. ID. NO. 11] on glioblastoma cell density was also examined. The FGFRof-exon specific antisense oligonucleotide (RlAS cont ) [SEQ. ID. NO. 10] in the reverse orientation was an important control because it maintained an identical base composition to the effective antisense oligonucleotide. It is believed that its lack of effectiveness in suppressing cell growth was the result of its inability to specifically hybridize to the target message . Figure 1 shows that the addition of the FGFR2- initiation site exon-specific antisense oligonucleotide (R2ASini) [SEQ. ID. NO. 12] had no effect on glioblastoma cell growth, but it significantly reduced the cellular density of the human neuroblastoma cell line SH-SY5Y in culture (Figure 6) . It was further demonstrated (Figure 5) that the SH-SY5Y cell line expresses FGFR2 mRNA and that this mRNA was selectively reduced by the FGFR2- initiation site exon-specific antisense oligonucleotide. Figure 6 demonstrates that the FGFR2 antisense oligonucleotide was effective in inhibiting cell growth in the SH-SY5Y neuroblastoma cell line, but not effective in inhibiting growth of the human glioblastoma cell lines which were devoid of FGFR2 mRNA (Figure 1) . These results demonstrated that the FGFR2-initiation site antisense oligonucleotide is effective in inhibiting cell growth of cells expressing FGFR2. Therefore, the absence of an effect on glioblastoma cells by the R2ASini oligomer in culture suggests that inhibition of cell growth was not due to non-specific effects of antisense oligomers and that addition of an antisense oligonucleotide, even one complementary to a related FGFR family member, was not sufficient to suppress cell growth. The addition of FGFRlβ antisense oligonucleotide to glioblastoma cells had no effect on cellular density (Fig. 1) . This finding was not consistent in view of the observation that as astrocytic cells transform and progress from a normal cell to a malignant glioblastoma cell, the cells shift their expression of FGFRl from an a predominant isoform (three immunoglobulin domains) to the β predominant isoform (two immunoglobulin domains) . The β form represents as much as 70% to 90% of the FGFRl message (32,33) . The lack of an effect on cellular growth using the FGFRlβ antisense oligonucleotide was as inconsistent a finding as finding an effect with the FGFRlα antisense oligonucleotide, since this α isoform represents a small fraction of the total message pool in human glioblastomas. Example 4 Effect of Claimed Oligomers on FGFRl mRNA Synthesis The purpose of this Example was to determine the effects on FGFRl mRNA synthesis of introducing a FGFRlα antisense oligomer to glioblastoma cells. Using the general methods described above, it was demonstrated that the addition of the FGFRlα-exon-specific antisense phosphorothioate oligonucleotide [SEQ. ID. NO. 1] selectively reduced the expression of FGFRl mRNA (Figure 4) . In contrast, the FGFRlα-exon-specific antisense phosphorothiate oligonucleotide in the reverse orientation [SEQ. ID. NO. 10] had no effect on FGFRl mRNA levels, consistent with its inability to suppress growth (Figure 4) . In experiments in which antisense oligonucleotide was added to the cells for three consecutive days and in which cell density was monitored for the subsequent two weeks, it was demonstrated that when the FGFRlα-exon- specific antisense phosphorothiate oligonucleotide [SEQ. ID. NO. 1] was not replenished, growth of the glioblastoma cells was reinitiated (Fig. 3) and this correlated with re-expression of FGFRl mRNA (Fig. 4, days 10 and 14) . Therefore, there was a clear correlation between the growth of the glioblastoma cells and their expression of FGFRl mRNA. Example 5 Effect of Claimed Oligomers on FGFR2 mRNA Synthesis The purpose of this Example was to examine the effects on FGFR2 synthesis of introducing the FGFRlα antisense oligomer to neuroblastoma cells. Using the methods described above, it was demonstrated that addition of the claimed FGFRlα-exon- specific antisense phosphorothioate oligonucleotide [SEQ. ID. NO. 1] did not affect the expression of FGFR2 mRNA in the human neuroblastoma cell line SH-SY5Y (Fig. 5) . Since FGFR2 is closely related in gene sequence and protein function to FGFRl, this demonstrates that the FGFRlα oligomer can distinguish between the two mRNAs on the basis of their sequences. The cell line used, SH- SY5Y expresses FGFR2, but does not express FGFRl. This further demonstrated the sequence-dependent action of the claimed FGFRlα-exon-specific oligonucleotide. Using the glioblastoma cell line, SNB-19, it was demonstrated that addition of FGFRlα-exon specific antisense oligonucleotide (SEQ ID NO. 1) had no effect on the levels of basic fibroblast growth factor protein in the SNB-19 cells (Fig. 7) . This demonstrated that the FGFRlα oligomer (SEQ ID NO. 1) did not non-specifically disrupt the FGFRl/bFGF autocine loop present in SNB-19 cells. The cells treated with FGFRlα oligomer had inhibited FGFRl production, but it did not inhibit production of the ligand bFGF which was still produced (as demonstrated by Figure 7) . This is more of a demonstration of chemical specificity than antisense (sequence) specificity, since the FGFRl and bFGF genes are not believed to be related. Basic fibroblast growth factor is a mitogen that has previously been shown to promote the growth of human glioblastoma cells. The above results demonstrated a specific action, i.e. suppressing glioblastoma cell growth by the FGFRlα antisense oligonucleotide [SEQ. ID. NO. 1] through diminution of FGFRl mRNA when, using the claimed method, the FGFRlα antisense oligomer [SEQ. ID. NO. 1] was brought into contact with tumor cells expressing the human FGFRl gene. Example 6 Effect of Claimed Antisense Oligomer on Growth of T98 Human Glioblastoma Cells The purpose of this study was to determine the effect of the FGFRlα antisense phosphorothioate oligomer [SEQ. ID. NO. 1] on the growth of another line of human glioblastoma cells, namely T98 cells. T98 cells were cultured and their numbers measured as described above. 30 μM FGFRlα-exon antisense oligonucleotide was added to the T98 cells. Cell densities were measured on days 1 and 7. As shown in Figure 8, the addition of the FGFRlα antisense oligomer (A5α) [SEQ. ID. NO. 1] resulted in a 34% reduction in cell number. No effect was observed with the control antisense oligonucleotide (AScont) [SEQ. ID. NO. 10] . Example 7 Specificity of FGFRl Alpha Exon Antisense Oligomer on Expression of FGFR Genes The purpose of this work was to determine the selectivity of the FGFRlα-exon antisense phosphorothioate oligomer [SEQ. ID. NO. 1] on the expression of other FGFR genes in glioblastoma cells. This was done to rule out suspected cross-hybridization between the FGFRlα-exon antisense oligomer and other FGFR family member mRNAs, which could have led to the suppression of growth. Cells were treated as described above. mRNA was analyzed as described above with the exception that both FGFRl, FGFR3 and FGFR4 mRNA were studied in this particular work. SNB-19 glioblastoma cells were plated at 1 x 10 s cells per 100mm dish in serum-supplemented medium. Eighteen hours later the cells were converted to serum-free medium containing FGFRlα antisense oligonucleotide (RIASα, 30μm) [SEQ. ID. NO. 1] or FGFRlα antisense reverse control oligonucleotide (RlαRC, 30μm) [SEQ. ID. NO. 10] . Non- treated cells (NT) were run as a control. Cells were treated for three consecutive days with oligonucleotide. Cells were scraped on day 7 and mRNA and cDNA were purified and synthesized respectively. Using cDNA from each of the three different treatments, PCR was used to amplify cDNA for FGFRl, FGFR3 , and FGFR4 receptors. SNB- 19 cells do not produce FGFR2. As shown in Figure 9, FGFRl mRNA was suppressed while there was no effect on expression of the FGFR3 and FGFR4 gene, i.e the level of FGFR3 and FGFR4 mRNA was not diminished. Figure 9 further shows no diminishment of the expression of the GAPDH (glyceraldehyde 3-phosphate dehydrogenase) locus which was used as a non-specific control. The findings demonstrated the specificity of the FGFRlα-exon antisense oligomer for the single and intended member of the FGFR family, namely FGFRl mRNA. In particular, it was demonstrated that treatment with FGFRlα antisense oligonucleotide suppressed FGFRl expression, whereas the reverse control oligonucleotide had no effect on FGFRl expression. In addition, FGFRlα antisense oligonucleotide did not suppress the expression of FGFR3 or FGFR4 , demonstrating the selective action of the claimed molecules' action on FGFRl. Although not limited to this explanation, it appeared that the significance of this finding was that the inhibition of growth was due only to the suppression of FGFRl, which is the intended target of this invention. Example 8 Using the general methods referred to above, antisense oligomers having a greater or lesser number of substituent nucleotides, or that extend further along the FGFRl pre-mRNA or mRNA in either the 3' or 5' direction than the oligomers of [SEQ. ID. NOS. 1 and 15 to 19] , or which comprise a sequence which is substantially complementary to and specifically binds to at least a portion of the targeted FGFRl alpha exon are introduced to tumor cells expressing the FGFRl gene. Introduction of the claimed antisense oligomers to tumor cells in suitable formulations described herein using therapeutic applications also described herein is found to suppress the growth of tumor cells in a variety of glioblastomas. Example 9 Assay of Oligomer Activity Against FGFRl and Cell Growth The procedure for measuring oligonucleotide activity against FGFRl and cell growth was as follows: SNB-19 cells were plated into polystyrene 96 well tissue culture plates (Corning cat. #25860) at a starting density of approximately 1,000 cells per well. The cells were allowed to recover and adhere to the glass overnight in normal growth medium. Normal growth medium consists of sterile filtered opti-MEM ® I (Gibco BRL, cat. #31985- 013) with 10% fetal bovine serum (Gemini Bio-Products, cat. #100-107) and with 10 ug/mL of streptomycin and 10 I.U./ml of penicillin Mediatech, cat. #30,001-LI) . Unformulated, free-in-solution oligonucleotide treatments were started the next morning by rinsing the cells thoroughly twice with 200 uL of PBS (Mediatech, cat. #21-031-LM) or serum-free medium (Opti-MEM ® I minus serum and antibiotics) . 200 uL of 30 uM all-phosphorothioate oligonucleotide in serum-free medium was added to each well. The 200 uL of oligonucleotide-containing serum-free medium in each well was replaced every 24 hours for three days with an additional 200 uL of 30 uM oligonucleotide in serum-free medium. After the fourth day (96 hours total exposure to oligonucleotides) the medium was left on the cells without changing for two additional days (48 hours) . Standard white-light observation of the cells after 6 days exposure to antisense and control oligonucleotides easily identified the active antisense oligonucleotides. The active lots of antisense oligonucleotides produced cultures that have very few cells, and the cells in the wells are rounded-up and poorly attached to the glass substrate. Typical numbers were from 60% to 90% inhibition of cell proliferation. No control oligonucleotide inhibited cell proliferation significantly or caused the significant rounding-up of cells. For quantitation of cell numbers, CellTiter 96 assays (Promega cat. #G5421) were used according to the manufacturer's instructions. In all cases, the visual impression of reduced cell proliferation was confirmed by the commercial cell titer assay. Example 10 Determination of Uptake of Oligomers The method for evaluating unformulated FITC- oligonucleotide uptake is as follows : SNB-19 cells were plated into 16 well/glass bottom slides (Nunc #178599) at a starting density of approximately 1,000 cells per well. The cells were allowed to recover and adhere to the glass overnight in normal growth medium. Normal growth medium consisted of sterile filtered OptiMEM ® I (Gibco BRL, cat. #31985-013) with 10% fetal bovine serum (Gemini Bio-Products, cat. #100-107) and with 10 ug/mL of streptomycin and 10 I.U./ml of penicillin Mediatech, cat. #30-001-LI) . Unformulated, free-in-solution FITC-oligonucleotide (FITC-oligo) treatments were started the next morning by rinsing the cells thoroughly twice with 200 uL of PBS (Mediatech, cat. #21-031-LM) or serum-free medium (Opti- MEM ® I minus serum and antibiotics) . 200 uL of 30 uM FITC-labeled oligonucleotide in serum-free medium was added to each well. Another serum- free medium that works well is RPMI Medium 1640, Gibco BRL, cat. #11835-022. The 200 uL of FITC-oligonucleotide-containing serum- free medium in each well was replaced every 24 hours for three days with an additional 200 uL of 30 uM FITC- labeled oligonucleotide in serum-free medium. After the fourth day (96 hours total exposure to FITC- oligonucleotides) the medium was left on the cells without changing for two additional days (48 hours) . The location of fluorescently labeled oligonucleotides within the SNB-19 human glioblastoma cells was viewed with a Nikon Labophot microscope with an Epi-fluorescent EF-D Mercury (Nikon Inc.) attachment after 6 days of FITC-oligonucleotide treatment. Clear detection of fluorescent oligonucleotides in the majority of cell nuclei is evidence of delivery of biologically active quantities of oligonucleotides. The cells were prepared for viewing as follows: The wells were emptied by shaking, the cells were fixed in 3.7% formaldehyde (Sigma Chemicals) , rinsed in PBS, and then the plastic chambers were removed and the rubber gasket lifted off of the glass. Fluoromount-G mounting medium (Fisher catalogue #OB1000, with photobleaching inhibitors) was used as mounting medium. We easily saw nuclei, endosomes and lysosomes under 200X magnification. Successful uptake was indicated by spectacular fluorescence within the nuclei of almost all cells in the culture. Unsuccessful uptake was evidenced by punctate fluorescence in endosomes and lysosomes throughout the cell, and in particular in a perinuclear crescent of terminal lysosomes. In these cases, no nuclear fluorescence was visible. Having thus disclosed exemplary embodiments of the present invention, it should be noted by those skilled in the art that this disclosure is exemplary only and that various other alternatives, adaptations, and modifications may be made within the scope of the present invention. Accordingly, the present invention is not limited to the specific embodiments as illustrated herein, but is only limited by the claims. Bibliography (Listed in Sequential Order As Appears and as referenced by numbers in Text) (1) Takahashi, J.A., Mori, H., Fukumoto, M., Igarashi, K. , Jaye, M., Oda, Y., Kikuchi, H. , and Hatanaka, M. Gene Expression of Fibroblast Growth Factors in Human Gliomas and Meningiomas: Demonstration of Cellular Source of Basic Fibroblast Growth Factor mRNA and Peptide in Tumor Tissue, Proc. Nat. Acad. Sci . USA (1990) 87:5710-5714. (2) Maxwell, M., Nabor, S.P., Wolfe, H.J., Hedley-Whyte, E.T., Galanopoulos, T., Neville-Goldon, J., and Antoniades, H.N. Expression of Angiogenic Growth Factor Genes in Primary Human Astrocytomas May Contribute to Their Growth and Progression, Cancer Research 51:1345- 1351 (1991) . (3) Yamanaka, Y., Friess, H., Buchler, M., et al. Overexpression of Acidic and Basic Fibroblast Growth Factors in Human Pancreatic Cancer Correlates With Advanced Tumor Stage, Cancer Res . 53:5289-5296 (1993) . (4) Houssaint, E., Blanquet, P.R. Champion-Arnaue, P., Gesnel, M.C. Torriglia, A., Courtois, Y., and Breathnach, R., Related fibroblast growth factor receptor genes exist in the human genome, Proc . Na tl . Acad . Sci . U. S . , 87: 8180-8184 (1990) . (5) Johnson, D.E., Lu, J., Chen, H., Werner, S., and Williams, L.T., The human fibroblast growth factor receptor genes: common structural arrangement underlines the mechanisms for generating receptor forms that differ in their third immunoglobulin domain, Mol . Cell Biol .. 11: 4627-4634 (1991) . (6) Keegan, K. , Johnson, D.E., Williams, L.T., and Hayman, M.J., Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3, Proc. Natl. Acad. Sci. USA. 88: 1095-1099 (1991) . (7) Partanen, J., Makela, T.P., Eerola, E., Korhonen, J., Hirvonen, H., Claesson-Welsh, L., and Alitalo, K. , FGFR-4, A novel acidic fibroblast growth factor receptor with a distance expression pattern, EMBO J. , 10: 1347- 1354 (1991) . (8) Ruta, M., Burgess, W., Bivol, D., Epstein J., Neiger, N., Kaplow, J. Crumley, G., Dionne, C, Jaye, M. , and Schlessinger, J., Receptor for acidic fibroblast growth factor is related to the tyrosine kinase encoded by the fms-like gene (FLG) , Proc. Natl, Acad. Sci. USA. 86: 8722-8726 (1989) . (9) Miki, T., Bottaro, D.P., Fleming, T.P., Smith, C.L., Burgess, W.H. , Chan, A.M.L., ad Aaronson, S.A., Determination of legand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene, Proc. Natl. Acad. Sci. USA. 89: 246-250 (1992) . (10) Morrison, R.S., Gross, J.L., Herblin, W.F., Reilly, T.M., LaSala, P.A., Alterman, R.L., Moskal, J.R., Kornblith, P.L., and Dexter, D.L., Basic fibroblast growth factor-like activity and receptors are expressed in a human glioma cell Line, Cancer Res. , 50: 2524-2529 (1990) . (11) Holt et al., Mol . Cell Biol . 8:963-973 (1988) , and Wickstrom et al. , Proc. Natl . Acad. Sci . USA, 85:1028-1- 32 (1988) . (12) Zamecnik and Stephenson, Proc . Natl . Acad. Sci . USA, 75:280-284 (1978) and Zamecnik et al . , Proc. Natl . Acad. Sci . USA, 83:4143-4146 (1986) . (13) Morrison, R.S. Suppression of basic fibroblast growth factor expression by antisense oligodeoxynucleotides inhibits the growth of transformed human astrocytes. J. Biol . Chem. , 266: 728-734 (1991) . (14) Murphy, P.R., Sato, Y., and Knee, R.S., Phosphorothioate antisense oligonucleotides against basic fibroblast growth factor inhibit anchorage-dependent and anchorage-independent growth of a malignant glioblastoma cell line, Mol . Endocrinol . , 6: 877-884 (1992) . (15) Becker, D., Lee., P.L., Rodeck, U. , and Herlyn, M. (1992)) Inhibition of the Fibroblast Growth Factor Receptor 1 (FGFRl) Gene in Human Melanocytes and Malignant Melanomas Leads to Inhibition of Proliferation and Signs Indicative of Differentiation, Oncogene 7:2303- 2313) . (16) John Goodchild, Conjugates of Oligonucleotides and Modified Oligonucleotides: A Review of Their Synthesis and Properties, Bioconiugate Chemistry, Volume 1 No. 3, May/June (1990) . (17) Kan M., DiSorbo D., Hou J., Hoshi H., Mansson P.E., and McKeehan W.L., High and low affinity binding of heparin-binding growth factor to a 130-kDa receptor correlates with stimulation and inhibition of growth of a differentiated human hepatoma, Cell J Biol Chem (1988) 263:11306-11313. (18) Moscatelli D., High and low affinity binding sites for basic fibroblast growth factor on cultured cells: Absence of a role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells, J Cell Physiol (1987) 131:123-130. (19) Vlodavsky I., Folkman J., Sullivan R., et al. , Endothelial cell-derived basic fibroblast growth factor: Synthesis and deposition into subendothelial extra cellular matrix, Proc Natl Acad Sci USA (1987) 84:2292- 2296. (20) Yayon A., Klagsbrun M., Esko J.D., Leder P., and Ornitz D.M., Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor, Cell (1991) 64:841-848. (21) Rapraeger A.C., Krufka A., and Olwin B.B., Requirement of heparin sulfate for BFGF-mediated fibroblast growth and myoblast differentiation, Science (1991) 252:1705-1708. (22) Johnson, D.E. and William L.T., Structural and Functional Diversity in the FGF Receptor Multigene Family. Advances in Cancer Research 60:1-41 (1993) . (23) Halaban R. , Ghosh S., and Baird A., bFGF is the putative natural growth factor for human melanocytes In Vitro Cell Dev. Biol. (1987) 23:47-52. (24) Rubin J.S., Osada H., Finch P.W., Taylor W.G., Rudikoff S., and Aaronson S.A., Purification and characterization of a newly identified growth factor specific for epithelial cells, Proc Natl Acad Sci USA (1989) 86:802-806. (25) Peters K.G. , Werner S, . Chen G., and Williams L.T., Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse, Development (1992) 114:233-243. (26) Werner S., Duan D-S. R. , de Vries C, Peters K.G. , Johnson D.E., and Williams L.T., Differential splicing in the extracellular region of fibroblast growth factor receptor 1 generates receptor variants with different ligand-binding specificities, Mol Cell Biol (1992) 12:82-88. (27) Eisemann A., Ann J.A. , Graziani G., Tronick S.R., and Ron D., Alternative splicing generates at least five different isoforms of the human basic-FGF receptor, Oncogene (1991) 6:1195-1202. (28) Hou J., Kan M., Wang F, et al . , Substitution of putative half-cystine residues in heparin-binding fibroblast growth factor receptors, J " Biol Chem (1992) 267 (25) :17804-17808. (29) Lai C, and Lemke G., An extended family of protein- tyrosine kinase genes differentially expressed in the vertebrate nervous system, Neuron (1991) 6:691-704 (30) Peters K.G., Werner S., Chen G., and Williams L.T., Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development (1992) 114:233-243) . (31) Adnane, J. , Guadray, P., Dionne, C.A., Crumley, G., Jaye, M., Schlessinger, J., Jeanteur, P., Birnbaum, D., and Theillet, C. BEK and FLG, Two Receptors to Members of the FGF family, Are Amplified in Subsets of Human Breast Cancer, Oncogene 6:659-663 (1991) . (32) Yamaguchi et al . PNAS 91:484 (1994) (33) Morrison et al . Cancer Research 54:2794 (1994) . (34) Stein et al . , Nucl . Acids Res . , 16:3209-3221 (1988) . (35) Blake et al . , Biochemistry 24 : 6132-6138 (1985) . (36) Morvan et al . , Nu l . Acids Res . . 14:5019-5032 (1986) . (37) Monia et al . Evaluation of 2' -modified oligonucleotides containing 2' deoxy gaps as antisense inhibitors of gene expression. J. Biol. Chem. 268:14514- 14522 (1933) . (38) Asseline et al . , Proc . Natl Acad. Sci . USA 81:3297- 3201 (1984) . (39) Knorre et al . , Biochemie 67:783-789 (1985) (40) Vlassov et al . , Nucl . Acids Res . 14:4065-4076 (1986) . (41) Knorre et al . , supra , and Vlassov et al . , supra. (42) Webb et al . , Nucl . Acids Res . 14 :7661-7674 (1986) . (43) Boutorin et al . , FEBS Letter' s 172:43-46 (1984) . (44) Chi-Hong et al . , Proc . Natl . Acad. Sci . USA 83:7147-7151 (1986) . (45) Chu et al., Proc . Natl . Acad. Sci . 82:963-967 (1985) . (46) Domb, A.J., Implantable Biodegradable Polymers for Site-specific Drug Delivery, p.l, Polymeric Site-Specific Pharmacotherapy, J. Wiley and Sons, 1994. (47) Brem, H., Walter, A., Tamargo, A., Olivi, R. and Langer, R., Drug Delivery to the Brain, p. 117, Polymeric Site-Specific Pharmacotherapy, J. Wiley and sons, 1994. (48) Tamargo, B.H., Olivi, A., Pinn, M., Weingart, J.D., Whara , M. , Epstein, J, I., Biodegradable Polymers for Controlled Delivery of Chemotherapy With and Without Radiation Therapy in the Monkey Brain, J. Neurosurg (US) 80 (2) :238-290 (1994) . (49) Tamargo, R.J., Mysero, J.S., Epstein, J.I., Yang, M.B., Chasin, M., and Brem, H. Interstitial Chemotherapy of the 9L Gliosarcoma: Controlled Release Polymers for Drug Delivery In the Brain, Cancer Res. (US) 53(2) :329- 333 (1993) . (50) Bouvier, G., Penn, Kroin, J.S., Beique, R.A. , Guerard, M.-J., Lesage, J., Appl . Neurophysiol . 50:223- 226 (1987) . (51) Berger, M.S., Spence, A.M., Stelzer, K.J., "Brain Tumors," in Current Therapy in Hematology/Oncology, eds. Brain, M.C. and Carbone, P.P., publ . Mosby Publishers, Inc. , Phil . (52) Pharmacokinetics and Cancer Therapy, eds. P. Workman and M.A. Graham, volume 17 in Cancer Surveys, Cold Spring Harbor Laboratory Press, 1993 and in Pharmacokinetics, Milo Gibaldi and Donald Perrier, eds., 2nd ed., Marcel Dekker, Inc. publ., New York, 1982. (53) Gross, J.L., Behrens, D.L., Mullins, D.E., Kornblith, P.L., and Dexter, D.L., Plasminogen activator and inhibitor activity in human glioma cells and modulation by sodium butyrate, Cancer Res. 48:291-296, 1988. (54) Egholm, et al. Peptide Nucleic Acids (PNA) - Oligonucleotide Analogues with an Achiral Peptide Backbone, (1992) ) . (55) Isacchi et al . 1990. (56) Erolani et al . , 1988. (57) Van der krol, A.R. et al . , Biotechniques 6(10) :958- 988, 1988. (58) Gray, D.W. et al . , J. Neurochem 6J3 (4) : 1354-1360 (October, 1994) . (59) Patterson, J.B. et al. , Virology 10.(2) :508-511 (July, 1995) . (60) Patterson, J.B. et al. , Mol . Cell Biol . 15.(10) : 5376- 5388 (October, 1995) . SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: GENTA INCORPORATED Morrison, Richard S. (ii) TITLE OF INVENTION: METHODS AND COMPOSITION FOR TREATING TUMOR CELLS (iii) NUMBER OF SEQUENCES: 19 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Lyon & Lyon (B) STREET: 633 West Fifth Street Suite 4700 (C) CITY: Los Angeles (D) STATE: California (E) COUNTRY: U.S.A. (F) ZIP: 90071 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: 3.5" Diskette, 1.44 Mb storage (B) COMPUTER: IBM Compatible (C) OPERATING SYSTEM: IBM P.C. DOS 5.0 (D) SOFTWARE: Word Perfect 5.1 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: To Be Assigned (B) FILING DATE: 10 JANUARY 1996 (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: 08/371,001 (B) FILING DATE: 10 JANUARY 1995 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: BIGGS, SUZANNE L. (B) REGISTRATION NUMBER: 30,158 (C) REFERENCE/DOCKET NUMBER: 218/068-PCT (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (213) 489-1600 (B) TELEFAX: (213) 955-0440 (C) TELEX: 67-3510 (2) INFORMATION FOR SEQ ID NO:1 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS : single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (iv) ANTISENSE: Yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: CTGCACATCG TCCCGCAGCC 20 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 base pairs (β) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: CGAGCTCACT GTGGAGTATC CATG 24 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: GTTACCCGCC AAGCACGTAT AC 22 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: AAGTGTGCAG ATGGGATTAA CGTC 24 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: ATTACCCGCC AAGCACGTAT AT 22 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: ACGGATTTGG TCGTATTGGG 20 (2) INFORMATION FOR SEQ ID NO:7 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid ( i) SEQUENCE DESCRIPTION: SEQ ID NO:7 : TGATTTTGGA GGGATCTCGC 20 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ϋ) MOLECULE TYPE: Other Nucleic Acid (xi) SEQUENCE DESCRIPTION SEQ ID NO:8: ATAACGGACC TTGTAGCCTC C 21 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: GGTCGTTTCA TCTGCCTGGT C 21 (2) INFORMATION FOR SEQ ID NO:10: (l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: CCGACGCCCT GCTACACGTC 20 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (iv) ANTISENSE: Yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: CGTCTTGACC CTACACCTCG 20 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (iv) ANTISENSE: Yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: GGCATTGGTA CCAGTCGACC C 21 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (iv) ANTISENSE: Yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: GCTCCACATC CCAGTTCTGC 20 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2733 base pairs (B) TYPE* nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 210.. 67 (D) OTHER INFORMATION: FGFRl Alpha Exon (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 57 (D) OTHER INFORMATION: "IDENTITY OF NUCLEOTIDE PROVISIONAL" (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 117 (D) OTHER INFORMATION: "IDENTITY OF NUCLEOTIDE PROVISIONAL" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: CGAGGCGGAA CCTCCAGCCC GAGCGAGGGT CAGTTTGAAA AGGAGGATCG AGCTCANCTG 6 TGGAGTATCC ATGGAGATGT GGAGCCTTGT CACCAACCTC TAACTGCAGA ACTGGGNATG 12 TGGAGCTGGA AGTGCCTCCT CTTCTGGGCT GTGCTGGTCA CAGCCACACT CTGCACCGCT 180 AGGCCGTCCC CGACCTTGCC TGAACAAGCC CAGCCCTGGG GAGCCCCTGT GGAAGTGGAG 240 TCCTTCCTGG TCCACCCCGG TGACCTGCTG CAGCTTCGCT GTCGGCTGCG GGACGATGTG 300 CAGAGCATCA ACTGGCTGCG GGACGGGGTG CAGCTGGCGG AAAGCAACCG CACCCGCATC 360 ACAGGGGAGG AGGTGGAGGT GCAGGACTCC GTGCCCGCAG ACTCCGGCCT CTATGCTTGC 420 GTAACCAGCA GCCCCTCGGG CAGTGACACC ACCTACTTCT CCGTCAATGT TTCAGATGCT 480 CTCCCCTCCT CGGAGGATGA TGATGATGAT GATGACTCCT CTTCAGAGGA GAAAGAAACA 540 GATAACACCA AACCAAACCG TATGCCCGTA GCTCCATATT GGACATCCCC AGAAAAGATG 600 GAAAAGAAAT TGCATGCAGT GCCGGCTGCC AAGACAGTGA AGTTCAAATG CCCTTCCAGT 660 GGGACCCCAA ACCCCACACT GCGCTGGTTG AAAAATGGCA AAGAATTCAA ACCTGACCAC 720 AGAATTGGAG GCTACAAGGT CCGTTATGCC ACCTGGAGCA TCATAATGGA CTCTGTGGTG 780 CCCTCTGACA AGGGCAACTA CACCTGCATT GTGGAGAATG AGTACGGCAG CATCAACCAC 840 ACATACCAGC TGGATGTCGT GGAGCGGTCC CCTCACCGGC CCATCCTGCA AGCAGGGTTG 900 CCCGCCAACA AAACAGTGGC CCTGGGTAGC AACGTGGAGT TCATGTGTAA GGTGTACAGT 960 GACCCGCAGC CGCACATCCA GTGGCTAAAG CACATCGAGG TGAATGGGAG CAAGATTGGC 1020 CCAGACAACC TGCCTTATGT CCAGATCTTG AAGACTGCTG GAGTTAATAC CACCGACAAA 1080 GAGATGGAGG TGCTTCACTT AAGAAATGTC TCCTTTGAGG ACGCAGGGGA GTATACGTGC 1140 TTGGCGGGTA ACTCTATCGG ACTCTCCCAT CACTCTGCAT GGTTGACCGT TCTGGAAGCC 1200 CTGGAAGAGA GGCCGGCAGT GATGACCTCG CCCCTGTACC TGGAGATCAT CATCTATTGC 1260 ACAGGGGCCT TCCTCATCTC CTGCATGGTG GGGTCGGTCA TCGTCTACAA GATGAAGAGT 1320 GGTACCAAGA AGAGTGACTT CCACAGCCAG ATGGCTGTGC ACAAGCTGGC CAAGAGCATC 1380 CCTCTGCGCA GACAGGTAAC AGTGTCTGCT GACTCCAGTG CATCCATGAA CTCTGGGGTT 1440 CTTCTGGTTC GGCCATCACG GCTCTCCTCC AGTGGGACTC CCATGCTAGC AGGGGTCTCT 1500 GAGTATGAGC TTCCCGAAGA CCCTCGCTGG GAGCTGCCCT CGGGACAGAC TGGTCTTAGG 1560 CAAACCCCTG GGAGAGGGCT GCTTTGGGCA GGTGGTGTTG GCAGAGGCTA TCGGGCTGGA 1620 CAAGGACAAA CCCAACCGTG TGACCAAAGT GGCTGTGAAG ATGTTGAAGT CGGACGCAAC 1680 AGAGAAAGAC TTGTCAGACC TGATCTCAGA AATGGAGATG ATGAAGATGA TCGGGAAGCA 1740 TAAGAATATC ATCAACCTGC TGGGGGCCTG CACGCAGGAT GGTCCCTTGT ATGTCATCGT 1800 GGAGTAGCCT CCAAGGGCAA CCTGCGGGAG TACCTGCAGG CCCGGAGGCC CCCAGGGCTG 1860 GAATACTGCT ACAACCCCAG CCACAACCCA GAGGAGCAGC TCTCCTCCAA GGACCTGGTG 1920 TCCTGCGCCT ACCAGGTGGC CCGAGGCATG GAGTATCTGG CCTCCAAGAA GTGCATACAC 1980 CGAGACCTGG CAGCCAGGAA TGTCCTGGTG ACAGAGGACA ATGTGATGAA GATAGCAGAC 2040 TTTGGCCTCG CACGGGACAT TCACCACATC GACTACTATA AAAAGACAAC CAACGGCCGA 2100 CTGCCTGTGA AGTGGATGGC ACCCGAGGCA TTATTTGACC GGATCTACAC CCACCAGAGT 2160 GATGTGTGGT CTTTCGGGGT GCTCCTGTGG GAGATCTTCA CTCTGGGCGG CTCCCCATAC 2220 CCCGGTGTGC CTGTGGAGGA ACTTTTCAAG CTGCTGAAGG AGGGTCACCG CATGGACAAG 2280 CCCAGTAACT GCACCAACGA GCTGTACATG ATGATGCGGG ACTGCTGGCA TGCAGTGCCC 2340 TCACAGAGAC CCACCTTCAA GCAGCTGGTG GAAGACCTGG ACCGCATCGT GGCCTTGACC 2400 TCCAACCAGG AGTACCTGGA CCTGTCCATG CCCCTGGACC AGTACTCCCC CAGCTTTCCC 2460 GACACCCGGA GCTCTACGTG CTCCTCAGGG GAGGATTCCG TCTTCTCTCA TGAGCCGCTG 2520 CCCGAGGAGC CCTGCCTGCC CCGACACCCA GCCCAGCTTG CCAATCGGGG ACTCAAACGC 2580 CGCTGACTGC CACCCACACG CCCTCCCCAG ACTCCACCGT CAGCTGTAAC CCTCACCCAC 2640 AGCCCCTGCT GGGCCCACCA CCTGTCCGTC CCTGTCCCCT TTCCTGCTGG CAGCCGGCTG 2700 CCTACCAGGG GCCTTCCTGT GTGGCCTGCT TCA 2733 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (iv) ANTISENSE: Yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: GCACATCGTC CCGCAGCC 18 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (iv) ANTISENSE: Yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: ACATCGTCCC GCAGCC 16 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (iv) ANTISENSE: Yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: CGTCCCGCAG CC 12 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: Other Nucleic Acid (iv) ANTISENSE: Yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: GCACATCGTC CCGCAGCCGA 20 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ϋ) MOLECULE TYPE: Other Nucleic Acid (iv) ANTISENSE: Yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: CTGCACATCG TCCCGC 16

Claims: Claims 1. An oligomer useful for inhibiting the growth of tumor cells, said oligomer specifically binding to a sequence portion of RNA expressed from the human FGFRl gene, which oligomer, when brought into contact with tumor cells expressing the human FGFRl gene has the property of reducing the expression of at least one FGFRl gene product and thereby suppressing the growth of said cells. 2. An oligomer of claim 1 wherein said oligomer is substantially complementary to and binds to the FGFRl pre-mRNA. 3. The oligomer of claim 1 wherein said oligomer is substantially complementary to and binds to the FGFRl alpha exon pre-mRNA. 4. The oligomer of claim 3 wherein said sequence portion of RNA comprises the FGFRl alpha exon, said oligomer having a sequence selected from SEQUENCE ID NOS. 1 and 15 to 19. 5. The oligomer of claim 1 wherein said oligomer is an oligonucleotide or an analog thereof. 6. The oligomer of claim 5 wherein the oligonucleotide is selected from the group consisting of deoxyribonucleotides and ribonucleotides. 7. The oligomer of claim 5 wherein said analog comprises at least one modification selected from the group of modifications consisting of 2'-0-alkyl sugar modifications, methylphosphonates, phosphorothioates, phosphorodithioates, formacetals, 3' -thioformacetals, sulfones, sulfamates, nitroxide backbone modifications, amides, base moiety modifications, morpholinos, peptide nucleic acids, and chimeras or conjugates thereof. 8. A composition useful for inhibiting the growth of tumor cells, comprising an oligomer specifically binding to a sequence portion of RNA expressed from the human FGFRl gene, which oligomer, when brought into contact with tumor cells expressing the human FGFRl gene has the property of reducing the expression of at least one FGFRl gene product and thereby suppressing the growth of said cells, together with a pharmaceutically acceptable carrier. 9. The composition of claim 8 wherein the oligomer is substantially complementary to and binds to the FGFRl pre-mRNA. 10. The composition of claim 8 wherein the oligomer is substantially complementary to and binds to the FGFRl alpha exon pre-mRNA. 11. The composition of claim 10 wherein said sequence portion of RNA comprises the FGFRl alpha exon, said oligomer having a sequence selected from SEQUENCE ID NOS. 1 and 15 to 19. 12. The composition of claim 8 wherein said oligomer is an oligonucleotide or an analog thereof. 13. The composition of claim 12 wherein said oligonucleotide is selected from the group consisting of deoxyribonucleotides and ribonucleotides. 14. The composition of claim 12 wherein said analog comprises at least one modification selected from the group of modifications consisting of 2'-0-alkyl sugar modifications, methylphosphonates, phosphorothioates, phosphorodithioates, formacetals, 3 ' -thioformacetals, sulfones, sulfamates, nitroxide backbone modifications, amides, base moiety modifications, morpholinos, peptide nucleic acids, and chimeras or conjugates thereof. 15. A vector for transfecting human tumor cells comprising a nucleotide sequence that encodes an antisense RNA which reduces expression from the human FGFRl gene in tumor cells. 16. The vector of claim 15 wherein said antisense RNA binds with a sequence portion of RNA expressed from the human FGFRl gene, which antisense RNA has the property of reducing the expression of at least one FGFRl gene product and thereby suppressing the growth of said cells . 17. The vector of claim 16 wherein said sequence portion comprises the FGFRl alpha exon. 18. The vector of claim 16 wherein said antisense RNA is substantially complementary to and binds to the FGFRl RNA. 19. A method for suppressing the growth of tumor cells, said method comprising the step of introducing an oligomer to tumor cells which express the FGFRl gene under conditions sufficient to reduce FGFRl gene expression in said tumor cells, said antisense oligomer being useful for inhibiting the growth of tumor cells, said oligomer specifically binding to a sequence portion of RNA expressed from the human FGFRl gene, which oligomer, when brought into contact with tumor cells expressing the human FGFRl gene has the property of reducing the expression of at least one FGFRl gene product and thereby suppressing the growth of said cells. 20. The method of claim 19 wherein said oligomer is substantially complementary to and binds to the FGFRl pre-mRNA. 21. The method of claim 19 wherein said oligomer is substantially complementary to and binds to the FGFRl alpha exon pre-mRNA. 22. The method of claim 21 wherein said sequence portion of RNA comprises the FGFRl alpha exon, said oligomer having a sequence selected from SEQUENCE ID NOS. 1 and 15 to 19. 23. The method of claim 19 wherein said antisense oligomer is an oligonucleotide or an analog thereof. 24. The method of claim 23 wherein the oligonucleotide is selected from the group consisting of deoxyribonucleotides and ribonucleotides. 25. The method of claim 23 wherein said analog comprises at least one modification selected from the group of modifications consisting of 2'-0-alkyl sugar modifications, methylphosphonates, phosphorothioates, phosphorodithioates, formacetals, 3' -thioformacetals, sulfones, sulfamates, nitroxide backbone modifications, amides, base moiety modifications, morpholinos, peptide nucleic acids, and chimeras or conjugates thereof. 26. The method of claim 19 wherein said oligomer is brought into contact with said cells under conditions where the concentration of said oligomer is from about 0.01 μM to about 50 μM. 27. The method of claim 19 wherein said step of introducing comprises the steps of: (a) removing a substantially large first portion of said tumor cells from a tumor whereby a second portion of tumor cells remains at the removal site; and (b) contacting said second portion of tumor cells with a sufficient amount of said oligomer to suppress the growth of said second portion of tumor cells. 28. A method for suppressing the growth of tumor cells, said method comprising the step of introducing an antisense RNA to tumor cells which express the FGFRl gene under conditions sufficient to reduce FGFRl gene expression in said tumor cells, wherein the step of introducing comprises: (a) transfecting said tumor cells with a vector comprising a sequence that encodes said antisense RNA; and (b) expressing said antisense RNA. 29. The method of claim 28 wherein said antisense RNA has a sequence which binds with a sequence portion of RNA expressed from the human FGFRl gene. 30. The method of claim 29 wherein said sequence portion of RNA comprises the FGFRl alpha exon. 31. A composition for inhibiting or decreasing proliferation or promoting initiation of cell death of glioma or glioblastoma cells which comprises an effective amount of an oligomer of about 10 to 30 nucleosides which is substantially complementary to and binds to FGFRl pre- mRNA and a pharmaceutically acceptable carrier. 32. A composition of claim 31 wherein said oligomer is a phosphorothioate oligomer. 33. A composition of claim 31 wherein said oligomer is selected from SEQ. ID. NOS. 1 and 15 to 19. 34. A composition of 33 wherein said oligomer is a phosphorothioate oligomer. 35. An oligomer of 10 to 30 nucleosides which is substantially complementary to and binds to FGFRl pre- mRNA. 36. An oligomer of claim 35 which is substantially complementary to and binds to the FGFRl alpha exon pre- mRNA. 37. An oligomer of claim 35 which has a sequence selected from SEQ. ID. NOS. 1 and 15 to 17. 38. An oligomer of claim 37 which is a phosphorothioate oligomer. 39. A method of inhibiting or decreasing proliferation or promoting cell death of glioma or glioblastoma cells which comprises contacting said cells or their environment with an effective amount to inhibit or decrease cell proliferation or increase cell death of a compound which selectively inhibits or prevents activity of FGFRl protein without substantially affecting activity of other FGFR proteins. 40. A method of claim 39 wherein said compound is an oligomer which is substantially complementary to and binds to FGFRl pre-mRNA.

Inventors: BROWN BOB D, MORRISON RICHARD S, TSENG BEN Y, BROWN, BOB, D., MORRISON, RICHARD, S., TSENG, BEN, Y.
Applicants: GENTA INC, MORRISON RICHARD S, GENTA INCORPORATED, MORRISON, RICHARD, S.
Application year: 1996
Main classification: A61K48
IPC codes: A61K38, A61K48, A61P35, C12N5, C12N15, C12Q1