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Contortrostatin, a Snake Venom Disintegrin, Inhibits ß₁ Integrin-mediated Human Metastatic Melanoma Cell Adhesion and Blocks Experimental Metastasis¹

Department of Biochemistry and Molecular Biology and University of Southern California Norris Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles, California 90033

Disintegrins are Arg-Gly-Asp-containing proteins that inhibit integrin-mediated cell-cell and cell-matrix interactions. We have purified a disintegrin, contortrostatin, from Agkistrodon contortrix contortrix snake venom that is a potent inhibitor of human metastatic melanoma (M24 met) cell adhesion to extracellular matrix proteins. Contortrostatin inhibits M24 met cell adhesion to type I collagen, vitronectin, and fibronectin with 50% inhibitory concentration values of 20, 75, and 220 nM, respectively. Contortrostatin does not significantly inhibit adhesion of M24 met cells to laminin. ¹²⁵I-labeled contortrostatin binds to M24 met cells in a saturable and displaceable manner. Scatchard analysis indicates that there are two binding sites for ¹²⁵I-labeled contortrostatin on the surface of these cells. High affinity binding has a K_d of 3 nM with 165,000 sites/cell; low affinity binding has a K_d of 60 nM with 500,000 sites/cell. Immobilized contortrostatin can support adhesion of M24 met cells; this binding is blocked by a monoclonal antibody to the ß₁ integrin subunit and by an antibody to the fibronectin receptor ₅ß₁. The anti-vitronectin receptor (_vß₅) monoclonal antibody which blocks adhesion of M24 met cells to immobilized vitronectin does not block binding of M24 met cells to immobilized contortrostatin. In an in vivo experimental metastasis model system, contortrostatin at 20 µg and 100 µg inhibits lung colonization of M24 met cells (5 x 10⁵), injected in the tail vein of scid mice, by 51 and 73%, respectively. We conclude that contortrostatin is a potent inhibitor of ß₁ integrin-mediated M24 met cell adhesion in vitro and that it also inhibits lung colonization in vivo.

¹ This work was supported by NIH Department of Health and Human Services Grants CA54861 (F. S. M., Y. A. D.) and CA42919 (Y. A. D).

² To whom requests for reprints should be addressed, at University of Southern California School of Medicine, Cancer Research Laboratory #106, 1303 North Mission Road, Los Angeles, CA 90033.

Received 2/ 3/94. Accepted 7/20/94.

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