INHIBITION OF METASTATIC CELL COLONIZATION IN MURINE LUNGS AND TUMOR-INDUCED MORBIDITY BY NONPEPTIDIC ARG-GLY-ASP MIMETICS

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 t he sub-endothelium extracellular matrix (ECM) and its glycoproteins. R ecognition of ECM-glycoproteins, such as fibronectin (FN) and vitronec tin (VN), is mediated by integrin receptors expressed on various cell types, including platelets, leukocytes and tumor cells. The Arg-Gly-As p (RGD)-containing peptide, a major adhesive ligand of ECM, is present in various plasma and matrix glycoproteins, such as FN and VN. Non-pe ptidic mimetics of RGD, consisting of carboxylate and guanidinium grou ps of Asp and Arg divided by a linear atom spacer, express a high affi nity for the alpha(IIb)-beta3 integrin and inhibit platelet aggregatio n. Herein, the ability of RGD mimetics to inhibit adhesive interaction s between tumor cells and RGD, and tumor progression in vivo, was exam ined. RGD-containing peptides and the RGD mimetic, compound SF-6,5, bu t not the Arg-Gly-Glu (RGE) peptide or the corresponding mimetic, spec ifically inhibited B16-F10 melanoma cell adhesion to immobilized VN an d FN. Daily administration in vivo of SF-6,S to mice inhibited the for mation of B16-F10 colonies in experimental and spontaneous models of m etastases. Moreover, SF-6,5 could prevent mouse death caused by massiv e colonization of tumor cells in the lungs. The therapeutic effect of RGD-containing peptides on tumor metastasis formation was marginal, pr obably due to the small amounts used, and its susceptibility to proteo lysis in situ. Thus, non-peptidic mimetics of small adhesive epitopes may provide a novel therapeutic tool to prevent an adverse pathologica l event involving integrin-dependent cell-cell and cell-ECM interactio ns. (C) 199-3 Wiley-Liss, Inc.