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Departments of Medical Biochemistry [T. I., M. K., M. O.], Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan Orthopedic Surgery [Y. I.], Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan Third Department of Internal Medicine, University of Tokushima, Tokushima 770-8583, Japan [H. N., Y. N., S. S.] Cancer Research Laboratory, Taiho Pharmaceutical Co., Saitama 357-8527, Japan [Y. Y.] SUGEN, Inc., South San Francisco, California 94080 [J. C., G. M.] Department of Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan [M. S.]

Interaction between vascular endothelial growth factor (VEGF) and its cognate receptors, KDR/Flk-1 and Flt-1, of vascular endothelial cells is expected to induce an angiogenesis "switch" in tumors and other angiogenesis-associated diseases. SU5416, a selective inhibitor of the KDR/Flk-1 tyrosine kinase, is known to be a potent inhibitor of tumor angiogenesis. In this study, we first observed that SU5416 inhibited Flt-1 tyrosine kinase activity at similar doses, in addition to inhibiting KDR/Flk-1 tyrosine kinase activity in response to VEGF. SU5416 inhibited cell migration of human vascular endothelial cells expressing both Flt-1 and KDR in response to VEGF and also inhibited the cell migration in response to placenta growth factor (PlGF), a specific ligand for Flt-1. Chemotaxis of monocytes expressing only Flt-1 was also inhibited by SU5416 in a dose-dependent manner. Moreover, SU5416 was found to inhibit tyrosine kinase of Flt-1 in response to PlGF in vitro. And angiogenesis induced by PlGF in a Matrigel plug assay was inhibited by administration of SU5416. The antiangiogenic effects by this VEGF receptor-targeting compound appeared to be mediated through interference not only with KDR/Flk-1 but also with Flt-1. Cell migration of vascular endothelial cells and monocytic cells through Flt-1, thus, might play a key role in VEGF-induced tumor angiogenesis in concert with KDR/Flk-1.

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