500. Local and systemic inhibition of lung tumor growth after liposome mediated mda-7/IL-24 gene delivery

The melanoma differentiation associated gene-7 (mda-7), also known as interleukin-24 (IL-24), is a novel gene with tumor suppressor, anti-angiogenic and cytokine properties. In vitro adenovirus-mediated gene transfer of the mda-7/IL-24 gene (Ad-mda7) results in ubiquitous growth suppression of human cancer cells with minimal toxicity to normal cells. Intratumoral administration of Ad-mda7 to lung tumor xenografts results in growth suppression via induction of apoptosis and anti-angiogenic mechanisms. Although these results are encouraging, one limitation of this approach is its locoregional clinical application-systemic delivery of adenoviruses for treatment of disseminated cancer is not feasible at the present time. An alternative approach that is suitable for systemic application is liposomal gene delivery. We recently demonstrated that DOTAP:cholesterol (DOTAP:Chol) liposomes effectively deliver tumor suppressor genes to primary and disseminated lung tumors. In the present study, therefore, we evaluated liposome-mediated delivery of the mda-7/IL-24 gene to primary and disseminated lung tumors in vivo. We demonstrate that DOTAP:Chol efficiently delivers the mda-7/IL-24 gene to human lung tumor xenografts resulting in suppression of tumor growth. Growth-inhibitory effects were observed in both primary (P = 0.001) and metastatic lung tumors (P = 0.02). Furthermore, tumor vascularization was reduced in mda-7/IL-24-treated tumors. Finally, growth was also inhibited in murine syngenic tumors treated with DOTAP:Chol-mda-7 complex (P = 0.01). This is the first report demonstrating (1) systemic therapeutic effects of mda-7/IL-24 in lung cancer and (2) anti-tumor effects of mda-7 in syngeneic cancer models. Our findings are important for the development of mda-7/IL-24 treatments for primary and disseminated cancers.