Therapeutic use of peptides having thrombospondin-like activity

Abstract: Methods for using synthetic analogs of thrombospondin for potentiating or inhibiting thrombospondin-like activity are provided.

Description: Technical Field The present invention relates generally to the use of polypeptides having thrombospondin (TSP)-like activity for the preparation of a medicament for treating tumors. The peptides retain and mimic the bioactivity of TSP as a potent potentiator or inhibitor of cell adhesion, cell migration, cell attachment, and cell spreading of different cell lines. The peptides also have the ability to inhibit platelet aggregation. In the presence of TSP, the peptides inhibit thrombospondin-like activity and in the absence of TSP, the peptides potentiate thrombospondin-like activity. The peptides find use in various biological and pharmacological applications. The applications include use as agents interfering with cancer development by inhibiting metastasis or causing regression of tumor growth. Furthermore the peptides are useful in the inhibition of platelet aggregation in the therapeutic areas of atherosclerosis and thrombosis; in inhibition of angiogenesis in the preparation of antibodies which are useful as diagnostic or therapeutic reagents, and in the promotion of inhibition of cellular attachment to surfaces. Background Thrombospondin (also known as thrombin sensitive protein or TSB) is a 450,000 molecular weight protein composed of three identical disulfide-linked polypeptide chains (Lawler et al. J. Cell Biol (1986) 101:1059-71). TSP is secreted by platelets in response to physiological activators such as thrombin and collagen (Lawler, J . Blood (1986) 67:112-123). TSP comprises 3% of the total platelet protein and 25% of the total platelet alpha granular protein (Tuszynski, G.P. et al. (1985) J . Biol. Chem. 260:12240-12245). Other cells also synthesize TSP including fibroblasts (Jaffe, E. A. et al., (1983) Natl. Acad. Sci. USA 80:999-1002), smooth muscle cells (Raugi, G. J. et al., (1982) J. Cell Biol. 95:351-354), and endothelial cells (McPhearson, J. et al. J . Biol. Chem. 256:11330-11336). TSP has been found in certain tumor tissues, such as melanoma cells (Varani, J. et al., (1989) Clin. Expl. Metastais 7:319-329), squamous lung carcinoma (Riser, B. L. et al., (1988) Exp . Cell Res. 174:319-329) and breast carcinoma (Pratt, D. A. et al., (1989) Eur. J . Cancer Clin . Oncol. 25:343-350). In addition, the following tumor cells in culture have been shown to synthesize TSP: fibrosarcoma, rhabdomyosarcoma, glioblastoma, Wilm's tumor, neuroblastoma, teratocarcinoma, choriocarcinoma, melanoma, and lung carcinoma (Mosher, D. F., (1990) Annu. Rev. Med. 41:85-97). A number of recent studies have shown that TSP plays a major role in cell-cell and cell substatum adhesion (Tuszynski, G. P. et al., (1987) Seminars in Thrombosis Hemostasis (13:361-368, Mosher, D. F., (1990) Annu . Rev. Med. 41:85-97). TSP promotes cell attachment, platelet aggregation, and lung tumor colony formation in a murine model of experimental metastasis (Tuszynski, G. P. et al., (1987) Science 236:1570-1573, Tuszynski, G. P. et al., (1988) Blood 72:109-115). The role of TSP in adhesion is further supported by the observation that the extracellular matrix of most tissues contains TSP. TSP is composed of linear polypeptide domains that specifically interact with various macromolecules such as plasma and matrix components. For example, TSP forms a complex with heparin (Yabkowitz, R. et al. (1989) J . Biol. Chem. 264:10888-10896), fibrinogen (Tuszysnki, G. P. et al. (1985) J . Biol . Chem. 260:12240-12245), collagen (Mumby, S. M. et al. (1984) J . Cell Biol. 98:10888-10896, and plasminogen (Depoli. P. et al. (1989) Blood 73:976-902). The structure of TSP is conserved among various animal species as indicated by the fact that the antiobody against the human protein cross-reacts with TSP from mouse, rat, pig, cow, sheep, dog, and turkey (Switalska, H. I. et al., J . Lab Clin. Med. 106:690-700). Thrombospondin has been purified by a number or procedures including exclusion chromatography (Lawler et al., J . Biol. Chem . (1978) 253:8609-16), heparin affinity chromatography (Lawler et al., Thromb. Res. (1981) 22:267-269), fibrinogen affinity chromatography (Tuszynski et al., J . Biol. Chem. (1985) 260:12240-5), barium chloride precipitation (Alexander et al., Biochem. J . (1984) 217:67-71) and anion exchange chromatography with HPLC (Clezarolin et al., J . Chromatog. (1984) 296:249-56). The complete amino acid sequence of TSP has been deduced from DNA clones prepared by various groups including Lawler et al., J . Cell Biol. (1986) 103:1635-48; Kobayashi et al., Biochemistry (1986) 25:8418-25; Dixit et al., Proc. Ntl. Acad. Sci. (1986) 83:5449-53; and Hennessy et al., J . Cell Biol. (1989) 108:729-36. Cell adhesion is critical to the development and survival of multicellular organisms. The process of cell adhesion is complex requiring numerous extracellular proteins such as fibronectin, vitronectin, collagen, laminin, and TSP and numerous families of cellular receptors such as the integrins and cellular adhesion molecules (CAMS). These molecules are involved in the adhesion of both normal and tumor cells and have been studied quite intensively in recent years. The amino acid sequence, Arg-Gly-Asp (RGD), was established as a cell attachment domain in fibronectin (Pierschbacher, M.D. and Ruoslahti, E., (1984) Nature (London) 309:30-32). The same or related sequences have been discovered in many proteins and serve as cell binding sites for such macromolecules as fibrinogen (Ginsberg, M. D. et al., (1985) J . Biol. Chem. 260:11891-11896). However, it appears that the adhesive function of laminin may not be based on the RGD sequence, but on a peptide segment of the B1 chain containing the amino acid sequence tyrosine-isoleucine-glycine-serine-arginine (YIGSR) (Sasaki, M. 1987, Proc. Natl. Acad. Sci 84:935-938). Synthetic peptides containing the RGD and YIGSR sequence promote cell adhesion. The therapeutic use of synthetic peptides based on the adhesive domains of fibronectin and laminin have recently been reported. Humphries et al. (2986) Science 233:467-470) were the first to demonstrate that co-injection of the pentapeptide GRGDS with B16-F10 murine melanoma cells dramatically inhibited the formation of lung colonies in C57BL/6 mice. Another synthetic peptide which was derived from laminin (YIGSR) also dramatically inhibited B16-F10 melanoma cell metastasis in C57B1/6 mice (Kleinman, H. K. et al., (1987) Science 238:1132-1133; Kleinman, H. K. et al., (1990) Proc. Natl. Acad. Sci. USA 87:2279-2283). The inhibitory activity of these peptides may be due to competition with endogenous laminin and fibronectin-dependent adhesion of tumor cells to the vascular bed of the target organ during the metastatic dissemination of the tumor cells. Because metastasis is a step-by-step process involving the transfer of tumor cells from one site to another through the lymphatic and blood circulation and platelet reduction in animals effectively blocked metastasis in animals (Gasic et al, (1968) Proc. Natl. Acad Sci USA 48:46-52), platelets have been thought to play a special role in the development of metastasis. Since TSP comprises 25% of the total alpha granular platelet secreted-protein, TSP would be expected to have a major role in the hemotagenous transfer of tumor cells to distant organs. Indeed, TSP has been shown to promote tumor cell metastasis in a murine model (Tuszynski et al, (1987) 47:4130-4133). In addition, events which accompany platelet activation, such as: secretion of adhesive proteins, platelet aggregation, activation of proteolytic enzymes, and activation of the clotting cascade have all been shown to play a significant role in tumor cell metastasis (Gasic, G. J., (1984) Cancer Metastasis Rev. 3:99-116). Adhesive proteins which are part of the extracellular matrix control the movement, growth, and morphology of many cell types. Extracellular matrix proteins interact with tumor cell receptors and affect tumor cell adhesion to basement membrane collagen in different ways. For example, exposure of melanoma cells in vitro to laminin resulted in increased capacity of tumor cells to adhere to the basement membrane and to produce lung tumor colonies (Barsky, S. H. et al., (1984) J . Clin. Inv. 74:843-848; Terranova, V. P. et al., (1984) Science 226:982-985). In view of the information described above, TSP may play an important role in many diverse and clinically important processes, such as: cell migration, wound healing, nerve regeneration, and tumor cell metastasis. To better understand the pathophysiology of these processes at the molecular level, assignment of each of the biological activities of TSP to a specific subdomain or oligopeptide of TSP would provide valuable information. Specifically, detailed knowledge of the structure of domains of the TSP and TSP receptors could be used to design TSP antagonist peptides which could block pathophysiological activities of TSP such as TSP-dependent tumor cell metastasis formation. TSP contains three homologous peptide sequences designated type I, II, and III repeats (Lawler and Hynes, (1986) J . Cell Biol. 103:1635-1648). The three repeats consist of approximately 60 amino acids each containing six cysteine residues. Type I repeats exhibit homology with peptide segments found in a number of diverse proteins. We have identified two hexapeptide sequences in TSP (CSTSCG and CSVTCG) that are either totally conserved in other proteins or present with one or two conservative amino acid substitutions in apparently unrelated proteins or encoded or predicted by their cdna sequence. The prevalence of the conserved sequences is indicated in Table I below. Protein Sequence Reference TSP CSVTCG CSTSCG Lawler et al., (1986), J . Cell Biol . 103:1635-48 Circumsporozoite CSVTCG Dame J. B. et al., (1984) Science 225:593-599 Trap CSVTCG Robson K. J. H. et al., (1988) Nature 335:79-82 Properdin CSVTCG Goundis, D. et al. (1988) Nature 335:82-85 Glycoprotein E Herpes simplex I CVVTCG McGoech D. J. et al, (1985) J . Mol . Biol . 181:1-13 Cytochrome C oxidase polypeptide II CSETCG Lawson, J. E. et al., (1985) Curr . Genet. 9:351-360 Respiratory nitrate reductase beta chain CSVTCK Blasco, F. et al. (1989) Mol. Gen. Genet. 218:249-256 Bird spider 18S ribosomal RNA CSVSCG Hendriks L. et al., (1989) Eur . J . Biochem. 177:15-20 Chicken alpha tubulin CSVVCG Lemischka I. R. et al. (1981) J . Mol . Biol . 151:101-120 Zebrafish homeobox gene CSKTCG Njolstad P. R. et al., (1990) EMBO J . 9:515-524 E. coli gut operon CSVTCX Yamada M. et al., (1987) Biol. Chem. 262:5455-5463 E. Coli ATPase CSVTCM Kanazawa H. et al., (1981) BBRC:103:613-620 Rat liver apolipoprotein A-I CSVGCG Poncin J. E. et al., (1984) Eur. J . Biochem. 140:493 Tryptophan synthetase CWVTCG Brosius, J. et al., (1982) Gene 17:223-228 Highlands J virus CSVTCL Ou J. H. et al., (1982) J . Mol. Biol. 156:719-730 Human c-myb proto-oncogene CSVTCK Slamon D. J. et al., (1986) Science 233:347-351 Antistasin CRKTCP CRVHCP Ginsberg V. et al. (1990) J . Biol. Chem. 264:12138-12140 Etp100 CVCECG Tomley F. et al (1989) 5th International Coccisiosis Conference 469-573 CSATCG CSRTCG CSEQCG Human desmin CSVTCH Li Z. et al., (1989) Gene 78:243-254 Human related mammary tumor virus CSVPCG May F. E. B. et al., J . Virol 60:743-749 Human protooncogane c-fes/fps CSRTCG Ouweland A. M. W. et al., EMBO J . 4:2897-2903 Platelet GPIIb CSVTCR Bray P. F. et al., (1987) J . Clin. Invest. 80:1812-1817 The present invention contemplates the use of polypeptides having thrombospondin like activity which mimic or inhibit the biological activity of intact thrombospondin which find use in the preparation of a medicament for treating tumors. Summary of the Invention It has now been found that a class of fragments or synthetic analogs from a specific domain of thrombospondin have a variety of uses. These polypeptides retain and mimic the bioactivity of TSP as a potent potentiator or inhibitor of cell adhesion, cell migration, cell attachment, and cell spreading. These polypeptides, by means of their adhesive activity, are capable of potentiating and inhibiting tumor cell growth and metastasis, cell adhesion, angiogenesis and platelet aggregation. The potentiation and inhibition properties of the peptides have been found to depend on the presence or absence of endogenous TSP. In the presence of endogenous TSP, the polypeptides inhibit thrombospondin-like activity. In the absence of TSP, the polypeptides promote thrombospondin-like activity. According to the present invention, the polypeptides are used for preparing a medicament for treating tumors. The TSP peptides and analogs used according to this invention have been shown to have thrombospondin-like activity. The present invention is, therefore, in one aspect directed to polypeptide compounds having thrombospondin-like activity which are indentified by the formula: R 1 -X 1 -X 2 -X 3 -X 4 -X 5 -R 2 wherein: R 1 is a protected or unprotected terminal amino group, including hydrogen, amino, acetyl or one amino acid residue or the desamino form thereof; X 1 X 5 and X 5 are cysteine X 2 , X 3 , and X 4 are the same or different amino acid residues selected from the group consisting of valine, threonine, serine, and arginine; R 2 is a protected or unprotected terminal carboxyl group including hydroxyl, carboxyl, amide or one amino acid residue, including carboxyamide or al kylamide forms thereof, preferably selected from the group consisting of lysine, glycine, and arginine; the structure of the polypeptide is optionally cyclized through a bond between the X 1 and X 5 , preferably a disulfide bond, or a bond between R 1 and R 2 . Administration of therapeutically effective doses of medicaments including the above mentioned TSP peptides and analogs can provide effective enhancement or inhibition of thrombospondin-like activity to animals, particularly vertebrates such as mammalian and avian hosts. Brief Description of the Drawings Figure 1 shows the results of HPLC analysis on peptide CSVTCG-NH 2 . Figure 2 shows the results of HPLC analysis on peptide CSVTCG. Figure 3 shows the results of HPLC analysis on peptide CSVTCG which is cyclized via a disulfide bond. Figure 4 shows the ability of the peptides of the invention to inhibit adhesion of melanoma cells. Figure 5 shows the ability of the peptides of the invention to act in collagen dependent melanoma cell adhesion. Figure 6 demonstrates that in vivo the peptides of the invention have antimetastatic activity. Figure 7 compares the lungs of mice treated with and without the peptides of the invention in the presence of melanoma cells. Figure 8 shows the ability of the peptides of the invention to inhibit ADP-induced platelet aggregation. Figure 9 shows the ability of the peptides of the invention to inhibit collagen-induced platelet aggregation. Figure 10 shows a dose response of the ability of peptide CSVTCG to inhibit collagen-induced platelet aggregation. Figure 11 shows the ability of the peptides of the invention to support the adhesion of human platelets. Figure 12 shows the ability of an antibody against a peptide of the invention to inhibit ADP-induced platelet aggregation. Figure 13 shows that in vivo an antibody against a peptide of the invention has antimetastatic activity. Detailed Description of the Invention In accordance with the present invention, a class of fragments and analogs of thrombospondin is used for preparing a medicament for treating tumors which is capable of inhibiting or mimicing the activity of thrombospondin in mammals in vivo. A. Definitions "Thrombospondin-like activity" is defined herein as any activity that mimics the known biological activities of thrombospondin. These activities include cell-adhesion promoting activity, cell mitogenic activity, cell chemotactic activities, and hemostatic activities and any activities that derive from these activities such as tumor cell, microbial, or parasite metastasis activity, platelet aggregating activity, fibrinolytic activity and immune modulation. "Cell adhesion activity" is defined herein as the ability to promote or inhibit the attachment of cells, preferably mammalian cells, to a substrate. "Platelet aggregation activity" is defined herein as the ability to inhibit the capacity of platelets to aggregate. "Antimetastatic activity" is defined herein as the ability to prevent or greatly reduce the extent or size of tumor cell metastasis, or inhibit or cause regression of primary solid tumors. "Atherosclerosis activity" is defined herein as the capacity of thrombospondin to inhibit atherosclerotic lesion formation. The atherosclerotic lesion is defined as the degenerative accumulation of lipid-containing materials, especially in arterial walls. "Antithrombotic activity" is defined herein as the ability to either inhibit the aggregation of platelets or to antagonize the formation of a thrombus. "Thrombolytic activity" is defined herein as the ability to disrupt the structure of a thrombus. "Angiogenesis activity" is defined herein as the ability to inhibit the formation of blood vessels or lymph vessels. The sequence of amino acid residues of the present polypeptide compounds, the core pentapeptide, and preferred embodiments thereof, are defined in terms of amino acids of certain characteristics of particular subclasses. Amino acid residues can be generally subclassified into four major subclasses as follows: Acidic, i.e., the residue has a negative charge due to loss of H ion at physiological pH and the residue is attracted by aqueous solution so as to seek the surface positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium. Basic, i.e., the residue has a positive charge due to association with H ion at physiological pH and the residue is attracted by aqueous solution so as to seek the surface positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium. Neutral/non-polar, i.e., the residues are not charged at physiological pH and the residue is repelled by aqueous solution so as to seek the inner positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium. Neutral/polar, i.e., the residues are not charged at physiological pH and the residue is attracted by aqueous solution so as to seek the outer positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium. It is understood, of course, that in a statistical collection of individual residue molecules some molecules will be charged, and some not. To fit the definition of charged, a significant percentage (at least approximately 25%) of the individual molecules are charged at physiological pH. Amino acid residues can be further subclassified as cyclic or non-cyclic, a self-explanatory classification with respect to the side chain substituent groups of the residues, and as small or large. The residue is considered small if it contains a total of three carbon atoms or less. Small residues are, of course, always non-cyclic. For the naturally occurring protein amino acids, subclassification according to the foregoing scheme is as follows: Acidic: Aspartic acid and Glutamic acid; Basic/non-cyclic: Arginine and Lysine; Basic/cyclic: Histidine; Neutral/polar/small: Glycine, Serine and Cysteine; Neutral/polar/large/non-cyclic: Threonine, Asparagine and Glutamine; Neutral/polar/large/cyclic: Tyrosine; Neutral/non-polar/small: Alanine; Neutral/non-polar/large/non-cyclic: Valine, Isoleucine, Leucine and Methionine; Neutral/non-polar/large/cyclic: Phenylalanine and Tryptophan. The protein amino acid proline, although within the classification neutral/non-polar/large/cyclic, is not included as an alternative due to its known effects on the secondary conformation of peptide chains. Certain commonly encountered non-natural amino acids, such as desamino Tyrosine (des Tyr), agmatine (Agm), n-formyl tryptophan (f-Trp), alpha-aminoisobutyric acid (Aib), and sarcosine (Sar), statine, ornithine (Orn), homolysine, homoserine, homoarginine, norleucine (Nle), norvaline may also be incorporated into the compounds of the invention. Desamino tyrosine is incorporated at the N-terminus. Agmatine and statine are incorporated at the C-terminus. Based on the above definition, n-formyl Trp is neutral/non-polar/large/ cyclic, Sar is neutral/non-polar/small, Aib is neutral/non-polar/non-cyclic, Orn is basic/non-cyclic, homolysine is basic/non-cyclic, homoserine is neutral/polar/small, homoarginine is basic/non-cyclic, norleucine is neutral/non-polar/large/non-cyclic, and norvaline is neutral/non-polar/large/non-cyclic. The nomenclature used to describe polypeptide compounds of the present invention follows the conventional practice wherein the amino group is presented to the left and the carboxy group to the right of each amino acid residue. In the formulae representing selected specific embodiments of the present invention, the amino- and carboxy-terminal groups, although not specifically shown, will be understood to be in the form they would assume at physiologic pH values, unless otherwise specified. In the amino acid structure formulae, each residue is generally represented by a one-letter or three-letter designation, corresponding to the trivial name of the amino acid, in accordance with the following schedule: Amino Acid Three-letter Symbol One-letter Symbol Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys C Glutamine Gln Q Glutamic acid Glu E Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methione Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V In the present application, the L-form of any amino acid residue having an optical isomer is intended unless otherwise expressly indicated, e.g., by the symbol "[D-X n ]." Compounds for use in the present invention can be obtained by modifying the disclosed formulae in numerous ways, while preserving the activity of the polypeptide compounds thus obtained. For example, while the amino acids of these compounds are normally in the natural L optical isomer form, one or more, usually two or less and preferably one amino acid may be replaced with the optical isomer D form, or a D,L-racemic mixture can be provided in the molecules comprising the polypeptide compound. Additionally, a disulfide linkage may be present or absent in the compounds used in the invention, as long as activity is maintained. As one skilled in the art would recognize, branched or cyclical chains may be produced by the formation of a peptide bond with amino acid side groups that contain amino or carboxyl moieties. Amino acids containing such side groups include, for example, glutamic acid (carboxyl group), aspartic acid (carboxyl group) and lysine (amide group). Branched or cyclical chains may also be produced through the formation of a covalent disulfide bond between amino acid residues having sulfur-containing side groups, such as cysteine. As used herein, "protected" terminal amino group, refers to a terminal amino group coupled with any of various amino-terminal protecting groups traditionally employed in peptide synthesis. Examples of suitable groups include acyl protecting groups, for example, formyl, acetyl, benzoyl, trifluoroacetyl, succinyl, and methoxysuccinyl; aromatic urethane protecting groups, for example, benzyloxycarbonyl; and aliphatic urethane protecting groups, for example, tert-butoxycarbonyl or adamantyloxycarbonyl. Gross and Mienhofer, eds., The Peptides , vol. 3, pp. 3-88 (Academic Press, New York, 1981), disclose numerous suitable terminal amino protecting groups. As used herein, "protected" terminal carboxyl group, refers to a terminal carboxyl group coupled with any of various carboxy-terminal protecting groups. As will be readily apparent to one skilled in the art, suitable groups include tert-butyl, benzyl or other acceptable groups linked to the terminal caroxyl group through an ester or ether bond. Amino acid residues contained within the compounds, and particularly at the carboxy- or amino- terminus, can also be modified by methylation, amidation, acetylation or substitution with other chemical groups which can, for example, change the circulating half-life, resistance to proteases and solubility of the compounds without adversely effecting their activity. In addition to the preceding definitions, the following abbreviations have been used throughout in describing the invention: BCA bicinchoninic acid BSA bovine serum albumin t-Boc t-butyloxycarbonyl Bzl benzyl °C degrees centigrade DCM dichloromethane DIEA diisopropyl ethyl amine DMEM Dulbecco's minimum essential medium DMF dimethyl formamide HF hydrogen fluoride HOBT 1-hydroxybenzotriazole HPLC high performance liquid chromatography mBHA methylbenzhydrylamine µ g microgram µ l microliter ml milliliter mM millimolar nm nanometers NMP N-methylpyrrolidone % percent PAM phenylacetamidomethyl PBS phosphate buffered saline TFA trifluoroacetic acid B. Preferred Embodiments The polypeptide compounds of the invention all contain the core pentapeptide sequence: R 1 -X 1 -X 2 -X 3 -X 4 -X 5 -R 2 wherein: R 1 is a protected or unprotected terminal amino group, including hydrogen, amino, acetyl or one amino acid residue or the desamino form thereof; X 1 and X 5 are cysteine X 2 , X 3 , and X 4 are the same or different amino acid residues selected from the group consisting of valine, threonine, serine, and arginine; R 2 is a protected or unprotected terminal carboxyl group including hydroxyl, carboxyl amide or one amino acid residue including carboxyamide or alkylamide forms thereof, preferably selected from the group consisting of lysine, glycine, and arginine; the structure of the polypeptide is optionally cyclized through a bond between the X 1 and X 5 , preferably a disulfide bond, or a bond between R 1 and R 2 . Particularly preferred are those embodiments wherein the sequence is selected from the group consisting of the following wherein the sequence includes C-terminal acid and amide forms, disulfide linked forms and blocked cysteine forms: The most preferred embodiments are selected from the group consisting of: Compounds to be used in the present invention can be synthesized chemically by means well known in the art such as, e.g., solid phase peptide synthesis. The synthesis is commenced from the carboxy-terminal end of the peptide using an alpha-amino protected amino acid. t-Butylocarbonyl (Boc) protective groups can be used for all amino groups even though other protective groups are suitable. See Stewart et al., "Solid-Phase Peptide Synthesis," W. H. Freeman Co., San Francisco (1969) and Merrifield, J . Am . Chem. Soc. 85: 2149-2154 (1963), Vale et al., Science 213, 1394-1397 (1981), and Marke et al., J . Am . Chem. Sci . 103, 3178 (1981). Other preparative methods which may be employed include the process of Houghton Proc. Natl. ACAD Sci. 82:5132 (1981), or another preferable synthesis procedure particularly for small branched or cyclic chain peptides which would include conventional liquid phase processes. The liquid phase process, as well as other synthesis methods are described in "Principle of Peptide Synthesis" M. Bodansky Ed. (Spring-Verlag 1984. These and other methods of peptide synthesis are also exemplified by U.S. Patents Nos. 3,862,925, 3,842,067, 3,972,859 and 4,105,602, 4,683,291, 4,244,946, and 4,305,872. Conveniently, compounds may be synthesized using manual techniques or automatically employing, for example, an Applied BioSystems 430A Peptide Synthesizer (Foster City, California) or a Biosearch SAM II automatic peptide synthesizer (Biosearch, Inc., San Rafael, California), following the instructions provided in the instruction manual supplied by the manufacturer. Although a purity of greater than 95 percent for the synthesized peptide is preferred, lower purity may be acceptable. To obtain cyclic peptides, where for example the two cysteine amino acids are bonded or where the residues contain a disulfide bridge which may be formed by oxidizing of a dilute aqueous solution of the peptide with K 3 [Fe(CN) 6 ]. Other means of cyclizing which are known in the art may also be utilized. The stabilized cyclized peptide of the present invention can also be prepared by forming a peptide bond between non-adjacent amino acid residue. A procedure for forming such peptide bond is provided in Schiller et al., Int. J . Peptide Protein Res. (1985) 25:171. Alternatively, selected compounds for use in the invention can be produced by expression of recombinant DNA constructs prepared in accordance with well-known methods. Such production can be desirable to provide large quantities or alternative embodiments of such compounds. C. Administration Compounds for use in the present invention have thrombospondin-like activity in the intact animal. Compounds for use in the present invention and medicaments containing them which are shown to have the physiological effect of inhibiting or mimicing the effect of intact thrombospondin find use in therapeutic and prophylactic applications, such as cancer therapy. Thus the present invention also provides for the use of such compounds including the nontoxic addition salts, amides and esters thereof, which may, alone, serve to provide the above-recited therapeutic benefits. In the preparation of medicaments, physiologically tolerable liquid, gel or solid diluents, adjuvants and excipients can be used. The medicaments prepared according to the present invention can be administered to animals for veterinary use, such as with domestic animals, and clinical use in humans in a manner similar to other therapeutic agents. In general, the dosage required for therapeutic efficacy will range from about 1 µg to 300 mg/kg, more usually 10 µg to 30 mg/kg of the host body weight. Alternatively, dosages within these ranges can be administered by constant infusion over an extended period of time, usually exceeding 24 hours, until the desired therapeutic benefits have been obtained. Typically, such medicaments are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared. The preparation may also be emulsified. The active ingredient is often mixed with diluents or excipients which are physiologically tolerable and compatible with the active ingredient. Suitable diluents and excipients are, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof. In addition, if desired, the medicament may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents, and the like. The medicaments are conventionally administered parenterally, by injection, for example, either subcutaneously or intravenously. Additional formulations which are suitable for other modes of administration include suppositories, intranasal aerosols, and, in some cases, oral formulations. For suppositories, traditional binders and excipients may include, for example, polyalkylene glycols or triglycerides: such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1%-2%. Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations, or powders, and contain 10%-95% of active ingredient, preferably 25%-70%. These oral formulations include formulations designed to protect the peptide until it can be absorbed. The polypeptide compounds may be formulated into the compositions as neutral or salt forms. Pharmaceutically acceptable non-toxic salts include the acid addition salts (formed with the free amino groups) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups may be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. The compounds used in the invention can be homopolymerized to themselves (i.e., (peptide)n) or, heteropolymerized to one another (i.e., peptide 1-peptide 2). The compounds can also be cyclized through disulfide or other means. The compounds can also be conjugated to biocompatible polymeric compounds, such as BIOPOL™ polymers (W.R. Grace & Co.-Conn.). While not wishing to be bound by any theory, it is believed that the medicaments prepared according to this invention act as agonists or antagonists to native thrombospondin. The polypeptides are also believed to act as agonists or antagonists to circumsporozoite protein, thrombospondin related anonymous protein, antistasin, and properdin complement protein. Further, since the compounds used in the invention are small in size (relative to intact thrombospondin) the properties which they exhibit are more likely to be specific in nature, as opposed to the actions of other generally adhesive compounds such as RGD containing compounds (the sequence of which is found in over a hundred proteins) and fibronectin. The side effects of the peptide compounds used in the invention are greatly reduced when compared with these broadly adhesive compounds. D. Use As stated previously, the medicaments prepared according to the invention can be used in a variety of biological, prophylactic or therapeutic areas. It is contemplated that these medicaments are useful in prevention or treatment of any disease state or conditions wherein thrombospondin-like activity plays a role. These disease states and conditions include, but are not limited to, cancer. Antibodies directed against the compounds used in this invention are also useful as diagnostic reagents, therapeutics, or carriers of other compounds. Numerous in vitro and in vivo assays can be used to demonstrate compounds having thrombospondin-like activity. These assays include, but are not limited to, cell adhesion assays, platelet aggregation assays and cell proliferation assays. METASTASIS Metastasis is the spread of disease from one part of the body to another unrelated to it, as in the transfer of the cells of a malignant tumor by way of the bloodstream or lymphatics. It is believed that metastasis is effected through a cascade mechanism which includes adhesion of tumor cells to endothelium, retraction of the endothelium, matrix degradation of the basement membrane and invasion of the tumor cells into the bloodstream. It is further speculated that the platelets play a major role in spreading the tumor cells in the bloodstream and effecting metastatic growth at sites distant from the primary tumor. Intervention at any phase in this cascade could be beneficial to the treatment or prevention of metastatic cancers. The native thrombospondin molecule has been shown to potentiate tumor cell metastasis (Tuszynski et al., Cancer Research (1987) 47:4130-4133). The mechanisms by which the thrombospondin potentiation occurs are not presently well understood. Antimetastasis activity is characterized by the ability of the compounds to bind to melanoma cells in vitro (Tuszynski et al., Anal. Bio. (1990) 184:189-91), and the ability to reduce the size and number of tumor colonies in vivo (Tuszynski et al. Cancer Research (1987) 47:4130-4133). The compounds used in this invention are useful as antimetastatic agents, particularly useful as anti-pulmonary metastatic agents. These compounds inhibit the adhesion of metastatic tumor cells, particularly those which are responsive to thrombospondin. The compounds also reduce tumor colony number as well as tumor colony size. There are a number of mechanisms by which such antimetastatic activity can be occurring. The peptides can be cytotoxic, or inhibit cell proliferation. As inhibitors of cell proliferation, the compounds can act to (1) inhibit mitogenesis, (2) inhibit angiogenesis, or (3) activate the complement pathway and the associated killer cells. It is also possible that, when the peptide inhibits platelet aggregation, it inhibits the ability of the platelets to interact with tumor cells and thus prevents the formation of platelet-tumor emboli which can seed distant organs. The compounds used in this invention can also find use in biomedical devices. Since the compounds have the ability to promote the attachment of metastatic tumor cells, it is possible to coat a biomedical device with the compounds to effect the removal of circulating tumor cells from blood or lymph. The biomedical device is also useful to trap hepatomas. Another use of the compounds is as a carrier to target toxins, drugs, hormones or imaging agents to metastatic tumor cells for diagnostic or therapeutic purposes. These carriers would also bind to hepatomas. The following examples are provided by way of illustration, rather than implying any limitation of the subject matter. EXAMPLES The peptides of this invention can be synthesized by conventional methods of peptide synthesis. The preferred conventional methods use the procedures described in Int . J . Pept. Proc . Res. 21 , 57-63 (1983). Also preferred is the solid phase synthesis of Merrified, J . Amer. Chem. Soc. 85 , 2149-2154 (1963); Science 150 , 178-185 (1965); Ibid . 232, 341-347 (1986). Solid phase synthesis is generally initiated from the C-terminal of the peptide by coupling a protected alpha amino acid to a suitable resin, e.g., phenylacetamidomethyl (PAM) polystyrene resin, or p-methylbenzhydrylamine (mBHA) resin when synthesizing a peptide with a C-terminal carboxyamide. During synthesis, suitable amino acid side-chain protecting groups are used as needed. Thus, aspartic acid is protected on the beta-carboxyl group as the benzyl ester and arginine is protected on the guanidino group by tosyl. After the desired peptide has been synthesized, the peptide is cleaved from the resin and protecting groups are removed by treatment with a reagent such as hydrogen fluoride (HF). The peptide can then be purified by high performance liquid chromatography (HPLC) or other such methods of peptide purification. Background information on the established procedures for solid phase peptide synthesis can be found in "Solid Phase Peptide Synthesis" by Stewart and Young, W. H. Freeman & Co., San Francisco, 1969. In accordance with the above description, the following procedures were used for the chemical synthesis of novel synthetic peptides: Example 1 Synthesis of the Peptide Sequence CSVTCG (SEQ ID NO:1) with C Terminal Amide An appropriate resin 4-methylbenzhydrylamine (MBHA) for C-terminal amide was sealed into polypropylene mesh packets (64 µ ). All packets were placed into a common vessel with CH 2 Cl 2 and vigorously shaken to wash and swell the resin. All subsequent steps involved vigorous shaking to ensure adequate solvent transfer. The N-α-butoxycarbonyl was then removed by acidolysis using 55% trifluoroacetic acid (TFA)/CH 2 Cl 2 for 30 minutes leaving the α-amino acid group in the TFA salt form. The packets were then washed with CH 2 Cl 2 (2x), IPA (2x), and CH 2 Cl 2 (2x) to remove excess TFA and prepare for neutralization. The IFA salt was neutralized by washing the packets three times with 5% diisopropylethylamine in CH 2 Cl 2 for 2 minutes each. This was followed by two washes with CH 2 Cl 2 to remove excess base. Packets were then removed from the common vessel and added to their respective 0.2 M amino acid solutions which were prepared from computer generated information prior to neutralization. An equal volume of 0.2 M dipropylcarbodiimide was then added to activate the coupling reaction. After coupling at room temperature for 1 hour, the packets were washed with dimethyl- formamide and CH 2 Cl 2 and returned to the common vessel. This process was repeated for each amino acid. Cleavage occurred by reacting the peptide with 92.5% hydrogen fluoride/7.5% anisole at -10°C to 0°C over 90 minutes. Anisole was used as a scavenger to react with carbocations produced as a result of the side chain protecting group removal. This solution was then removed using a strong flow of N 2 followed by the use of aspirator vacuum, while maintaining the temperature at 0°C. Residual anisole was removed with 2 ethyl ether washes. The peptide was then extracted using 10% acetic acid. The purity of the crude peptide was checked by analytical RP-HPLC using a Beckman System Gold with a Vydac C-18 column at a flow rate of lml/min. The solvent system used was 0.05% aqueous TFA(A) and 0.05% TFA in acetonitrile (B) with a gradient of 5-65% B in 30 minutes measuring the absorbance at 215 µ m). Purification was performed on Waters delta prep. 3,000 preparative HPLC with a Waters prep. Pak Nodule Radial Compression C18 column (25 cm x 5 cm, 10-20 µ ). The solvent system was 0.05% aqueous TFA (A) and 0.05% TFA in acetontrile (B). Various linear gradients were used measuring the absorbance at 230 nm and collecting 40 ml fraction. The fractions were then analyzed on the Beckman analytical system. The desired fractions were pooled and lyophilized. The final dry product was analyzed one more time using analytical RP-HPLC. Typical HPLC chromatograms for this peptide after purification are shown in Figure 1. Example 2 Chemical Synthesis of the Peptide Sequence CSVTCG Acid (SEQ ID NO:1) An appropriate resin phenylacetamidomethyl (PAM) for C-terminal acid was sealed into polypropylene mesh packets (64 µ ). All packets were placed into a common vessel with CH 2 Cl 2 and vigorously shaken to wash and swell the resin. All subsequent steps involved vigorous shaking to ensure adequate solvent transfer. The N-α-butoxycarbonyl is then removed by acidolysis using 55% trifluoroacetic acid (TFA)/CH 2 Cl 2 for 30 minutes leaving the α-amino acid group in the TFA salt form. The packets were then washed with CH 2 Cl 2 (2x), IPA (2x), and CH 2 Cl 2 (2x) to remove excess TFA and prepare for neutralization. The TFA salt was neutralized by washing the packets three times with 5% diisopropylethylamine in CH 2 Cl 2 for 2 minutes each. This was followed by two washes with CH 2 Cl 2 to remove excess base. Packets were then removed from the common vessel and added to their respective 0.2 M amino acid solutions which were prepared from computer generated information prior to neutralization. An equal volume of 0.2 M diisopropylcarbodiimide was then added to activate the coupling reaction. After coupling at room temperature for 1 hour, the packets were washed with dimethylformamide and CH 2 Cl 2 and returned to the common vessel. This process was repeated for each amino acid. Cleavage occurred by reacting the peptide with 91.5% hydrogen fluoride/7.5% anisole at -10°C to 0°C over 90 minutes. Anisole was used as a scavenger to react with carbocations produced as a result of the side chain protecting group removal. This solution was then removed using a strong flow of N 2 followed by the use of an aspirator vacuum, while maintaining the temperature at 0°C. Residual anisole is removed with two ethyl ether washes. The peptide is then extracted using 10% acetic acid. The purity of the crude peptide was checked by analytical RP-HPLC using a Beckman System Gold with a Vydac C-18 column at a flow rate of 1 ml/min. The solvent system used was 0.05% aqueous TFA(A) and 0.05% TFA in acetonitrile (B) with a gradient of 5-65% B in 30 minutes measuring the absorbance at 215 nm. Purification was performed on Waters delta prep. 3,000 preparative HPLC with a Waters prep. Pak Nodule Radial Compression C18 column (25 cm x 5 cm, 10-20 µ m). The solvent system was 0.05% aqueous TFA (A) and 0.05% TFA in acetonitrile (B). Various linear gradients were used measuring the absorbance of 230 nm and collecting 40 ml fraction. The fractions were then analyzed on the Beckman analytical system. The desired fractions were pooled and lyophilized. The final dry product was analyzed one more time using analytical RP-HPLC. Typical HPLC chromatogram for this peptide after purification are shown in Figure 2. Example 3 Synthesis of cyclic CSVTCG-Acid (SEQ ID NO:1) Cyclization of CSVTCG (SEQ ID NO:1) peptide was accomplished by dissolving the crude peptide of Example 2 (52 mg) in 500 ml deoxygenated water and the pH was adjusted to 8.5 with 28% NH 4 OH (solution A). K 3 Fe(CN) 6 (1.75 g) was dissolved in 100 ml deoxygenated water and the pH was adjusted to 8.5 with 28% NH 4 OH. This solution is called solution B. Solution A was dropped into solution B in 2 hours and the mixture was allowed to stir 1 more hour. The pH was then adjusted to 4 with 10% AcOH and the solution was injected onto a prep.-HPLC. After purification a 28 mg peptide of 95% purity has been recovered. The composition of the cyclic material was confirmed by analytical reverse phase HPLC and by Feb-MS. Typical HPLC chromatography is presented in Figure 3. Example 4 Chemical Synthesis of Additional Peptides Following the procedures outlined in Examples 1-3 and in Int. J . Pept. Proc. Res. 21, 57-65 (1983) with appropriate modification, the following peptides were synthesized. All peptides of the invention were tested for endotoxins using standard LAL assay procedures and found to be endotoxin free. Example 5 Adhesion of Various Cells to TSP and Peptides In this example a series of peptides were tested to determine the abilities of the peptides to bind various cells as compared to thrombospondin. It is believed that thrombospondin acts in metastasis through its adhesive properties. An assay was developed, generally in accordance with the disclosure of Tuszynski et al. ( Anal . Bio. (1990) 184:189-91) which evaluates the ability of cells to adhere to the thrombospondin fragments or analogs of the invention. In this assay, thrombospondin (purified by the method of Tuszynski et al., J . Biol. Chem. (1985) 260:12240-5) served as a positive control, bovine serum albumin (BSA) (Sigma Chemical Co.) and the peptides ANKHYF and VCTGSC and TCVCGS served as negative controls. The cell types evaluated were B 16 F 10 mouse melanoma cells, A549 human lung adrenocarcinoma cells, bovine aortic smooth muscle cells, and rabbit smooth muscle cells. Thrombospondin analogs of the invention were synthesized as described in Examples 1-4. Two micrograms of peptide or control proteins were air dried overnight on the wells of a 96-well microtiter plate. Wells were then washed with HEPES-buffered saline and blocked for 1 hour with 1% fatty acid free BSA in HEPES-buffered saline. The various cells were grown and harvested during log phase of growth using standard procedures. The harvested cells were washed two times in serum-free Dulbecco's minimum essential medium (DMEM) (Flow Laboratories) and suspended in HEPES-buffered saline, containing 5 mM glucose and 100 µ M MgCl 2 at a final concentration of 4 x 10 5 cells/ml. Of the cell suspension 200,000 cells per well was added to each well of the microtiter dish containing the various ligands and the dish incubated at 37°C in a CO 2 incubator for 30 minutes. Nonadherent cells were removed by aspiration and the wells washed three times with 200 µ l of PBS. The total cell-associated protein was determined by dissolving the attached cells directly in the microtiter wells with 200 µ l of the Pierce BCA working solution ( Pierce Chem. Co . Booklet No. 23225 (1987)). The plate was covered with an adhesive mylar sheet (Flow Labs) and incubated at 60°C for 30 minutes. Plates were allowed to cool to room temperature, cover sheets were removed, and the absorbance of each well was determined at 562 nm with a microtiter plate reader (Biotek, Burlington, Vermont.) Absorbances were converted to number of adherent cells by means of an empirically determined conversion factor. The results shown in Figure 4 graphically indicate that the peptides of the invention display adhesive properties to B 16 F 10 melanoma cells. The results in Table II indicate that the peptides of the invention display adhesive activity on all tested cell lines. Percent of TSP-adherent Cells Cell Type Compound B 16 -F 10 Mouse Melanoma A549 Human Lung Adenocarcinoma Bovine Aortic Endothelia 1 Cells Rabbit Smooth Muscle ANKHYF 8 10 0 17 VCTGSC 2 8 3 17 TCVCGS 10 10 6 8 CSVTCG (SEQ ID NO:1) 40 29 49 44 Cyclic CSVTCG (SEQ ID NO:1) 30 29 25 43 Blocked CSVTCG (SEQ ID NO:1) 32 44 22 46 CSVTCR (SEQ ID NO:2) 92 90 99 159 CSTSCR (SEQ ID NO:3) 39 104 65 82 CSTSCG (SEQ ID NO:4) 37 23 39 22 CRVTCG (SEQ ID NO:5) 92 79 80 82 ASVTAR (SEQ ID NO:7) 39 not tested not tested not tested Example 6 The Effect of Peptides on Collagen Dependent Adhesion of B 10 F 10 Melanoma Cells. Two micrograms of collagen in 5 mM acetic acid were adsorbed to wells overnight at 4°C. Wells were then washed with HEPES-buffered saline and blocked for 1 hour with 1% fatty acid free bovine serum albumin (BSA) in HEPES buffered saline. A suspension of B 16 F 10 cells in HEPES-buffered saline, containing 5 mM glucose (200,000 cells per well) and 100 µ M MnCl 2 were preincubated for 15 minutes at 37°C in either buffer or in buffer containing 100 µ g/ml peptide or 100 µ g/ml BSA. The cell suspensions were then added to collagen-coated wells and incubated for 30 minutes at room temperature. Non-adherent cells were removed by aspiration, and adherent cells determined by measurement of cell-associated protein as previously described in Example 5. The results shown in Figure 5 indicate that the peptides of the invention inhibit the binding of the melanoma cell to collagen. Example 7 The Effect of Peptides on B 16 F 10 Lung Tumor Cell Metastasis The in vivo model used to demonstrate the antimetastatic activity of the peptide compounds of the invention is described by Tuszynski et al. (Cancer Res. (1987) 47:4130-4133). Briefly, C57 black mice were intravenously injected with 1 x 10 5 B 16 F 10 mouse melanoma cells in the presence of either control buffer (Hepes buffered saline, pH 7.4), or 1 mg of the designated peptide compound of the invention. Five or six animals were used for each compound. Peptides tested in the assay had no effect on cell viability as measured by Trypan blue dye exclusion. In addition, the peptides at 1 mg/ml did not effect cell growth after 24 hours of co-culture. After 14 days, the mice were sacrificed and the number of lung tumors counted. The results shown in Figure 6 indicate the peptides of the invention have antimetastatic activity. The bar graphs show the mean number of lung tumors observed in the treatment groups and the error bars represent the standard error of the mean. Figure 7 shows representative lungs from each of the treatment groups. Example 8 Capillary Endothelial Cell Proliferation Assay The effect of the peptides of the invention on the proliferation of capillary endothelial cells in vitro were measured. Capillary endothelial cells are known to proliferate in response to angiogenic stimulus during neovascularization (Ausprunk et al., J. Microrasc . Res. (1977) 14:53). By using the specific cells involved in angiogenesis and stimulating them with a known angiogenesis factor, acidic fibroblast growth factor (aFGF), the angiogenesis process can be mimicked in vitro . The assay used was described by Moses et al. ( Science 1990) 248:1408-10). Doses of 0.01, 0.1, 1.0, 10, and 100 µ g/ml of the peptides of the invention CSVTCG (SEQ ID NO:1) and CSVTCR (SEQ ID NO:2) were tested. The most potent peptide was CSVTCR (SEQ ID NO:2) which showed 20% inhibition of stimulated endothelial cell proliferation at 10 µ g/ml and 100% inhibition at 100 µ g/ml. Peptide CSVTCG (SEQ ID NO:1) showed 39% inhibition at 100 µ g/ml. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Eyal, Jacob Hamilton, Bruce King Tuszynski, George Paul (ii) TITLE OF INVENTION: Therapeutic Use of Peptides Having Thrombospondin-line Activity (ii) NUMBER OF SEQUENCES: 14 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: W. R. Grace & Co.-Conn. (B) STREET: 7379 Route 32 (C) CITY: Columbia (D) STATE: Maryland (E) COUNTRY: USA (F) ZIP: 21044 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC Compatible (C) OPERATING SYTEM: PC-DOS/MS-DOS (D) SOFTWARE: Word Perfect 5.1 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: 530 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Appleby, Vanessa L. (B) REGISTRATION NUMBER: 33223 (C) REFERENCE/DOCKET NUMBER: 01-7900 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (301) 531-4515 (2) INFORMATION FOR SEQ ID NO:1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:

Claims: Use of a polypeptide having thrombospondin-like activity for the preparation of a medicament for treating tumors, the polypeptide having a sequence comprising the formula: R 1 -X 1 -X 2 -X 3 -X 4 -X 5 -R 2 wherein: R 1 is a protected or unprotected terminal amino group, including hydrogen, amino, acetyl or one amino acid residue or the desamino form thereof; X 1 and X 5 are C; X 2 , X 3 and X 4 are the same or different amino acid residues selected from the group consisting of R, S, T and V; R 2 is a protected or unprotected terminal carboxyl group including hydroxyl, carboxyl, amide, or one amino acid residue including carboxyamide or alkylamide forms thereof; the structure of the polypeptide is optionally cyclized through a bond between X 1 and X 5 or a bond between R 1 and R 2 . The use of claim 1 for the preparation of a medicament which inhibits tumor cell metastases. The use of claim 1 for the preparation of a medicament which inhibits tumor growth. The use of claim 1 for the preparation of a medicament which reduces tumor size. The use of claim 1 for the preparation of a medicament which reduces tumor colony number. The use of claim 1 wherein at least one of R 1 and R 2 is one amino acid residue. The use of claim 6 wherein the polypeptide compound is selected from the group consisting of: wherein each peptide can include C-terminal acid and amide forms, disulfide linked forms and blocked cystein forms. The use of claim 1 wherein said polypeptide compound is admixed with at least one pharmaceutically accetable carrier. The use of any of claims 1 to 8 wherein X 2 is selected from the group consisting of S and R, wherein X 3 is selected from the group consisting of R, T, and V, and wherein X 4 is selected from the group consisting of S and T.

Inventors: EYAL JACOB, HAMILTON BRUCE KING, TUSZYNSKI GEORGE PAUL, EYAL, JACOB, HAMILTON, BRUCE KING, TUSZYNSKI, GEORGE PAUL
Applicants: GRACE W R & CO, PHILADELPHIA HEALTH & EDUCATIO, PHILADELPHIA HEALTH AND EDUCATION CORPORATION, W.R. GRACE & CO.-CONN.
Application year: 1991
Main classification: C07K7
IPC codes: A61P7, C07K16, A61K38, A61P35, C07K14, C07K7