Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice

AdmATF is a recombinant adenovirus encoding a secreted version of the amino-terminal fragment (ATF) of murine urokinase (uPA). This defective adenovirus was used in murine models to assess the antitumoral effects associated with local or systemic delivery of ATF, a broad invasion inhibitor that antagonizes uPA binding to its surface receptor (UPAR). A single intratumoral injection of AdmATF into pre-established MDA-MB-231 human breast xenografts grown in athymic mice, or into pre-established C57/BL6 syngeneic Lewis lung carcinoma resulted in a specific arrest of tumor growth. Neovascularization within and at the vicinity of the injection site was also sup pressed, suggesting that AdmATF inhibitory tumor growth by targeting angiogenesis. AdmATF also interfered with tumor cell establishment at distant sites. (1) lung dis-semination of Lewis lung carcinoma cells was significantly reduced follow intratumoral injection at the primary site, and (2) systemic administration of AdmATF inhibited Subsequent fiver metastasis in a LS174T human colon caret noma xenograft model. These data outline the potential of using a recombinant adenovirus directing the secretion of an antagonist of cell-associated uPA for cancer gene therapy.