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 three murine models to assess the antitumoral effects associated with local or systemic delivery of ATF, a broad cell invasion inhibitor that antagonizes uPA binding to its cell 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 suppressed, suggesting that AdmATF inhibited primary tumor growth by targeting angiogenesis. AdmATF also interfered with tumor cell establishment at distant sites: (1) lung dissemination of Lewis lung carcinoma cells was significantly reduced following intratumoral injection at the primary site; and (2) systemic administration of AdmATF inhibited subsequent liver metastasis in a LS174T human colon carcinoma 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.