UROKINASE RECEPTOR ANTAGONISTS INHIBIT ANGIOGENESIS AND PRIMARY TUMOR-GROWTH IN SYNGENEIC MICE

Urokinase plasminogen activator (uPA) and its receptor are key compone nts of a cell surface proteolytic cascade used by tumor cells and capi llary endothelial cells for basement membrane invasion, a process requ ired for metastasis and angiogenesis. We have cloned, expressed, and p urified the epidermal growth factor-like domain of murine uPA alone an d fused it to the Fc portion of human IgG as high-affinity murine urok inase receptor antagonists. These molecules are potent inhibitors of m urine urokinase-binding to its receptor and inhibit angiogenesis in an ill vitro model of capillary tube formation in fibrin gels. In vivo, basic fibroblast growth factor-induced neovascularization and B16 mela noma growth in syngeneic mice are also substantially suppressed by the se molecules. Coupled with previous studies shoeing inhibition of meta stasis, these findings suggest that urokinase receptor antagonists may be useful therapeutically as inhibitors of tumor progression.