Inhibition of metastatic cell colonization in murine lungs and tumor-induced morbidity by non-peptidic 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 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.
Hardan
I
I
Department of Hematology, Chaim Sheba Medical Center, Tel-Aviv, Israel.
Weiss
L
L
Hershkoviz
R
R
Greenspoon
N
N
Alon
R
R
Cahalon
L
L
Reich
S
S
Slavin
S
S
Lider
O
O
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004151:Dipeptides; D005260:Female; D005353:Fibronectins; D006023:Glycoproteins; D006146:Guanidines / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D008546:Melanoma, Experimental / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology*; D014631:Valerates / Q000494:pharmacology*; D019096:Vitronectin
D004151:Dipeptides; D005353:Fibronectins; D006023:Glycoproteins; D006146:Guanidines; D009842:Oligopeptides; D014631:Valerates; D019096:Vitronectin; C084660:SF 6,5; C047981:arginyl-glycyl-aspartic acid; C084658:SFN 70