Inhibition of metastatic cell colonization in murine lungs and tumor-induced morbidity by non-peptidic Arg-Gly-Asp mimetics.

Abstract

The spreading and colonization of tumor cells require their migration to metastatic sites via blood vessels. To penetrate blood-vessel walls, cells, including malignant ones, must recognize and associate with the sub-endothelium extracellular matrix (ECM) and its glycoproteins. Recognition of ECM-glycoproteins, such as fibronectin (FN) and vitronectin (VN), is mediated by integrin receptors expressed on various cell types, including platelets, leukocytes and tumor cells. The Arg-Gly-Asp (RGD)-containing peptide, a major adhesive ligand of ECM, is present in various plasma and matrix glycoproteins, such as FN and VN. Non-peptidic mimetics of RGD, consisting of carboxylate and guanidinium groups of Asp and Arg divided by a linear atom spacer, express a high affinity for the alpha IIb-beta 3 integrin and inhibit platelet aggregation. Herein, the ability of RGD mimetics to inhibit adhesive interactions between tumor cells and RGD, and tumor progression in vivo, was examined. RGD-containing peptides and the RGD mimetic, compound SF-6,5, but not the Arg-Gly-Glu (RGE) peptide or the corresponding mimetic, specifically inhibited B16-F10 melanoma cell adhesion to immobilized VN and FN. Daily administration in vivo of SF-6,5 to mice inhibited the formation of B16-F10 colonies in experimental and spontaneous models of metastases. Moreover, SF-6,5 could prevent mouse death caused by massive colonization of tumor cells in the lungs. The therapeutic effect of RGD-containing peptides on tumor metastasis formation was marginal, probably due to the small amounts used, and its susceptibility to proteolysis in situ. Thus, non-peptidic mimetics of small adhesive epitopes may provide a novel therapeutic tool to prevent an adverse pathological event involving integrin-dependent cell-cell and cell-ECM interactions.

• Authors: I Hardan, L Weiss, R Hershkoviz, N Greenspoon, R Alon, L Cahalon, S Reich, S Slavin, O Lider
• Journal: International journal of cancer (Int J Cancer) Vol. 55 Issue 6 Pg. 1023-8 (Dec 02 1993) ISSN: 0020-7136 [Print] United States
• PMID: 7504656 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dipeptides
• Fibronectins
• Glycoproteins
• Guanidines
• Oligopeptides
• Valerates
• Vitronectin
• SF 6,5
• arginyl-glycyl-aspartic acid
• SFN 70

Topics

• Animals
• Cell Adhesion (drug effects)
• Dipeptides
• Female
• Fibronectins
• Glycoproteins
• Guanidines (pharmacology)
• Lung Neoplasms (prevention & control, secondary)
• Melanoma, Experimental (prevention & control, secondary)
• Mice
• Mice, Inbred C57BL
• Oligopeptides (pharmacology)
• Valerates (pharmacology)
• Vitronectin