Characterization of an immunocompetent mouse model for gene therapy in ovarian cancer

Gene therapy emerged as a promising therapy for ovarian cancer. One problem new therapies face is finding appropriate animal models that closely mimic the human disease.{09}Previous studies utilized nude mice to study the effects of intraperitoneal administration of Ad-CMV-p53 on tumors generated by human ovarian cancer cells and the role of NK cells in the bystander effect during gene therapy with Ad-CMV-p53. The role of NK and other immune cells is important when considering strategies of potentiating therapy effects.; Although nude mice have been intensely used to study human cancer, this model has limitations. The efficacy of multiple adenovirus injections and the role of the immune system during gene therapy cannot be studied because the model does not reflect what happens in the immunocompetent human patient. Therefore, we decided to investigate the efficacy and role of the immune system in gene therapy with Ad-CMV-p53 and Ad-IFNgamma in an immunocompetent mouse model of ovarian cancer.; Therapy with Ad-CMV-p53 and Ad-IFNgamma did not induce a significant survival advantage in immunocompetent mice given IG10 cells. Therefore, we did not pursue studies of immune cells like macrophages or NK cells during gene therapy. Instead, we proceeded with in vitro studies to determine why gene therapy in vivo was ineffective. In vitro studies suggested IG10 cells exhibit resistance at doses of IFNgamma in the range used for in vivo studies. Our results indicated that IG10 cells exhibit decreased susceptibility over time to nitric oxide when compared to other mouse or human ovarian cancer cells.; Resistance toward Ad-IFNgamma gene therapy was also suggested by high expression of antiapoptotic and cell cycle inhibiting genes after treatment with Ad-IFNgamma.; These studies are novel in an imunocompetent mouse model of ovarian cancer. Although therapy results were not satisfactory, they correspond to results obtained in human clinical trials with Ad-p53. New approaches should consider introduction of additional therapeutic genes together with more appropriate dosing schemes of adenoviral vectors and gene therapy-chemotherapy combinations.