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Multiple Roles for Platelet GPIIb/IIIa and vß3 Integrins in Tumor Growth, Angiogenesis, and Metastasis

Department of Biology Research, Centocor, Inc., Malvern, Pennsylvania 19355 [M. T., Z. Z., M. K., E. E., M. T. N.], and Department of Tumor Progression, National Institute of Oncology, Budapest, Hungary H-1122 [J. T., E. R.]

In vivo tumor cells interact with a variety of host cells such as endothelial cells and platelets, and these interactions are mediated by integrins GPIIb/IIIa and vß3. We used chimeric (c) 7E3 Fab (ReoPro) and murine (m) 7E3 F(ab')₂ to elucidate the role of these integrins in angiogenesis, tumor growth, and metastasis. These antibodies are potent inhibitors of GPIIb/IIIa and vß3. c7E3 Fab inhibited vß3-mediated human umbilical vein endothelial (HUVEC) and melanoma cell adhesion, migration, invasion, and basic fibroblast growth factor stimulated proliferation of HUVECs (IC₅₀ values range from 0.15 to 5 µg/ml for different assays). In an in vitro angiogenesis assay, c7E3 Fab inhibited basic fibroblast growth factor and platelet-stimulated capillary formation of HUVECs (IC₅₀ = 10 µg/ml and 15 µg/ml, respectively), demonstrating that endothelial vß3 is important for sprouting, and platelet-stimulated sprouting is mediated by GPIIb/IIIa. In an experimental metastasis assay, a single pretreatment of human melanoma cells with c7E3 Fab (2.5 µg/ml) inhibited lung colonization of the tumor cells in severe combined immunodeficient mice. In vivo, m7E3 F(ab')₂ partially inhibited growth of human melanoma tumors in nude mice compared with control-treated animals. These data suggest that tumor cell-expressed integrins are important but not the only component involved in tumor growth. Because c7E3 Fab and m7E3 F(ab')₂ do not cross-react with murine integrins, this inhibition of metastasis and tumor growth is attributable to direct blockade of human tumor vß3 integrins. m7E3 F(ab')₂ completely blocked tumor formation and growth of human melanoma tumors growing in nude rats. In this xenograft model, m7E3 F(ab')₂ simultaneously binds to both human tumor and host platelet GPIIb/IIIa and endothelial vß3 integrins, thus participating as an antiangiogenic and an antitumor agent. Collectively, these results indicate that combined blockade of GPIIb/IIIa and vß3 affords significant antiangiogenic and antitumor benefit.

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