In vivo therapy of malignant melanoma by means of antagonists of αv integrins

Abstract

Integrin αvβ3 (vitronectin receptor) has been implicated in human malignant melanoma progression and angiogenesis as a receptor that provides survival signals. However, little is known about the therapeutic potential of antagonists of αvβ3. In this report, we characterize the activities of 2 antagonists of αvβ3 integrins: a human specific monoclonal antibody (MAb), 17E6, and a cyclic RGD peptide that blocked cell adhesion and induced detachment of previously substrate-attached cells in vitro. In vivo, αvβ3 antagonists behaved as anti-tumor drugs in a dose- and time-dependent manner. Moreover, different therapeutic treatments proved to be effective even in the therapy of established macroscopic tumor masses, thus supporting the use of these antagonists in clinical therapy. Using a panel of 6 human melanomas and 5 carcinomas, MAb 17E6 efficiently blocked the in vivo tumor growth of melanomas expressing αvβ3 as xenografts but did not affect the αvβ3-negative (although αv integrin-positive) tumors. This demonstrated that αvβ3 is a pivotal integrin for the growth of human melanomas. Furthermore, since MAb 17E6 does not recognize murine αvβ3, the effect is due only to the direct anti-tumor activity and not to the well-known anti-angiogenic activity of αv-integrin antagonists. Taken together, our results confirm the essential role of αvβ3 integrin in the growth of human malignant melanoma in vivo and provide strong evidence of the therapeutic potential of αv-integrin antagonists for the treatment of such tumors. Int. J. Cancer 87:716–723, 2000. © 2000 Wiley-Liss, Inc.