Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Patent
1998-01-27
2000-11-14
Ungar, Susan
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
435 72, 435 721, 435 723, 435 29, 530300, 530326, 530327, C12Q 100, G01N 3353, A61K 3800
Patent
active
06146824&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention concerns anti-metastatic and anti-angiogenic pharmaceutical compositions. The compositions of the invention may be used in the treatment of cancer.
BACKGROUND OF THE INVENTION
Adhesive interactions of metastatic tumor cells with components of the extracellular matrix are required for successful target organ-colonization. The metastatic cells contact and subsequently adhere to substratum mainly via members of a family of proteins present on their membrane surface termed "integrins". A transmembrane link is established between the extracellular matrix and the cyto-skeletal cell machinery of the metastatic cell, wherein the integrin protein serves as a mediator
Integrins are activated by a motif of Arg-Gly-Asp (RGD) which is common to various adhesive molecules (Albelda and Buck, Fed. Am. Soc. Exp., 4:2868-80, (1990); Hynes, Cell, 69:11-25, (1992)).
Synthetic peptides containing the RGD motif present in short tetra-penta or hexa-sequences were found to be able to inhibit pulmonary colonization of metastatic cells (Humphries et al., Science, 233:467-470; (1986); Humphries et al., Clin. Invest. 81:782-790; (1988)). These short RGD-containing synthetic peptides were derived from the cell-binding domain of matrix molecules such as of fibronectin. It is believed that these synthetic peptides inhibit pulmonary colonization of tumor cells by acting as competitive, reversible inhibitors for the fibronectin receptor. The RGD-sequence derived from fibronectin is: )
Other known extracellular matrix components such as vitronectin collagens, laminin, and proteoglycans, which are known to promote cell adhesion and migration, are also believed to play a role in tumor cell invasion. Synthetic peptides containing the RGD sequence are capable of competing with each of these adhesion molecules for its receptor thereby inhibiting cell attachment and migration of both normal and tumor cells on substrates coated with these adhesion molecules (Yamada, K. M. and Kennedy, D. W., J. Cell Biochem., 28:99-104 (1985)); Piershbacher, M. D. and Ruoslahti, E, Nature, 309:30-33 (1984)).
Thrombin, the final activation product of the clotting cascade is responsible for converting fibrinogen to fibrin monomers that polymerize spontaneously to form a typical clot mesh. In addition to its major role in hemostasis, thrombin plays a role in the degradation of various constituents of extracellular matrix, induces cellular responses such as proliferation, chemotaxis as well as diverse cellular bioregulatory functions connected with wound healing and inflammation. Amino acid analysis of the thrombin B-chains reveals the presence of an Arg-Gly-Asp sequence at residues 187-189. The sequence adjacent to the RGD thrombin site being. ) adhesion molecules, native thrombin does not exhibit adhesive properties since, as evident by crystallographic analysis, the Gly-Asp residues of the RGD motif are buried within molecule (Bode et al., EMBO J., 8:3467-3475 (1989)).
We have previously shown (Bar-Shavit, et al., J. Cell Biol., 112(2):335-344 (1991)) that thrombin may be converted to form an adhesion molecule for endothelial cells (EC), probably after exposure of the cryptic RGD motif. This exposure can be carried out by incubation of thrombin with plasmin, by preparation of a thrombin analog (NO.sub.2 -.alpha. thrombin) obtained by nitration of the tyrosine residues. The adhesion of EC cell is mediated via the .alpha.,.beta..sub.3 receptor, present on endothelial cells' surface (Bar-Shavit, et al., supra (1991)).
Angiogenesis, the generation of new blood vessels, is a crucial factor in tumor growth and metastasis. It was shown that an angiogentic inhibitor, secreted from a primary tumor are able to reach a remote secondary tumor and as a result inhibit the secondary's tumor growth and its metastatic spread (O'Reilly et al., Cell, 79:315-328, (1994)). An example of another angiogenic inhibitors are thrombospondin (Tolsma et al., Cell Biol., 122:497-511, (1993) and Nickoloff et al., Am. J. Pathol., 144:820-828 (1994
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Hadasit Medical Research Services and Development Company Ltd.
Ungar Susan
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