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

I. Hardan, L. Weiss, R. Hershkoviz, N. Greenspoon, R. Alon, L. Cahalon, S. Reich, S. Slavin, O. Lider

Research output: Contribution to journalArticlepeer-review

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 α11b ‐β3 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 integrindependent cell‐cell and cell‐ECM interactions.

Original languageEnglish
Pages (from-to)1023-1028
Number of pages6
JournalInternational Journal of Cancer
Volume55
Issue number6
DOIs
StatePublished - 2 Dec 1993
Externally publishedYes

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