Urokinase receptor antagonists: discovery and application to in vivo models of tumor growth

Urokinase receptor antagonists based on the growth factor domains of both h uman and murine urokinase which show sub-nanomolar affinities for their hom ologous receptors have been expressed as recombinant proteins. Further modi fication of these molecules by preparing fusions with the constant region o f human IgG has led to molecules with high affinities and long in vivo half -lives. Smaller peptidic inhibitors have been obtained by a combination of bacteriophage display and peptide analog synthesis. All of these molecules inhibit the binding of the growth factor domain of uPA to the uPA receptor and enhance binding of the uPA receptor to vitronectin. Protein uPA recepto r antagonists were tested in an in vivo tumor model using the human breast carcinoma MDAmb231 in immunodeficient mice. Both human and murine receptor antagonists showed significant inhibition of primary tumor growth, demonstr ating that in vivo, both tumor and stromal cell uPA receptor dependent plas minogen activation can modulate tumor growth.