Effects of angiostatin gene transfer on functional properties and in vivo growth of Kaposi's sarcoma cells

Gene transfer delivery of endogenous angiogenesis inhibitors such as angios tatin would circumvent problems associated with long-term administration of proteins. Kaposi's sarcoma (KS), a highly vascular neoplasm, is an excelle nt model for studying tumor angiogenesis and antiangiogenic agent efficacy. We investigated the effects of angiostatin gene transfer in in vitro and i n vivo models of KS-induced neovascularization and tumor growth. A eukaryot ic expression plasmid and a Moloney leukemia virus-based retroviral vector for expression of murine angiostatin were generated harboring the angiostat in cDNA with cleavable leader signals under the control of either the stron g cytomegalovirus promoter/enhancer or the Moloney leukemia virus long term inal repeat. Angiostatin secretion was confirmed by radioimmunoprecipitatio n and Western blot analysis. Supernatants of angiostatin-transfected cells inhibited endothelial cell migration in vitro. Stable gene transfer of the angiostatin cDNA by retroviral vectors in KS-IMM cells resulted in sustaine d angiostatin expression and delayed tumor growth in nude mice, which was a ssociated with reduced vascularization. These findings suggest that gene th erapy with angiostatin might be useful for treatment of KS and possibly oth er highly angiogenic tumors.