| Adenovirus-mediated gene therapy is a promising approach for the treatment of ovarian cancer. Unlike many other cancers, ovarian cancer remains confined to the peritoneal cavity. This confinement makes it a disease highly amenable to intraperitoneal therapy, such as adenovirus-based gene therapy. Previous studies from our laboratory utilized an intraperitoneal administration of Ad-CMV-p53 for the treatment of nude mice harboring human ovarian cancer cells. Thus we hypothesize that intraperitoneal delivery of an adenovirus-based p53 gene therapy is both an efficacious delivery route and treatment for a model of early stage ovarian cancer. To further elucidate the mechanism of Ad-CMV-p53 treatment for ovarian cancer, it was important to determine the biodistribution of virus following an intraperitoneal administration. We found for the first time that introduction of adenovirus by intraperitoneal administration resulted in distribution of the adenovirus to the peritoneal organs and that the expression of the viral transgene persisted for 42 days post-infection. These results indicate long term expression of the viral transgene is possible using intraperitoneal adenovirus-based therapy. Interestingly, the complete elimination of cancer cells, in animal models, is often achieved, even though the therapeutic gene has not been delivered to all of the cancer cells. This is referred to as a bystander effect, because uninfected tumor cells near those that received the therapeutic gene are also eliminated. Our results indicated for the first time that immunological mechanisms involving natural killer cells play an important role in the bystander effect involving adenovirus-p53 gene therapy for ovarian cancer. In summary, we are the first to report that intraperitoneal doses of adenovirus deliver therapeutic genes to most cells and tissues in the peritoneal cavity. This route of administration also elicited an immune response by NK cell activation. These novel results indicate a synergism between delivery route, viral dissemination and a localized inflammatory response. Therefore, intraperitoneal delivery, via adenovirus, of a therapeutic gene such as p53 to cancer cells resident in the peritoneal cavity may lead to their elimination. |
