In vivo therapy of malignant melanoma by means of antagonists of alphav integrins.
Integrin alphavbeta3 (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 alphavbeta3. In this report, we characterize the activities of 2 antagonists of alphavbeta3 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, alphavbeta3 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 alphavbeta3 as xenografts but did not affect the alphavbeta3-negative (although alphav integrin-positive) tumors. This demonstrated that alphavbeta3 is a pivotal integrin for the growth of human melanomas. Furthermore, since MAb 17E6 does not recognize murine alphavbeta3, the effect is due only to the direct anti-tumor activity and not to the well-known anti-angiogenic activity of alphav-integrin antagonists. Taken together, our results confirm the essential role of alphavbeta3 integrin in the growth of human malignant melanoma in vivo and provide strong evidence of the therapeutic potential of alphav-integrin antagonists for the treatment of such tumors.
Merck Farma y Quimica, S.A. Laboratorio de Bioinvestigacion, Barcelona, Spain. francesc.mitjans@merck.de
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F
Mitjans
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Meyer
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Fittschen
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S
Goodman
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Jonczyk
J F
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Marshall
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Reyes
J
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Piulats
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000494:pharmacology; D019073:HT29 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology; D007700:Kinetics; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000502:physiology; D012910:Snake Venoms; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D016023:Integrins; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C064660:integrin alphaVbeta5; C094340:integrin alphavbeta1; C073878:integrin alphavbeta6; C422910:Cilengitide