Efficacy of intraperitoneal adenovirus-mediated p53 gene therapy in ovarian cancer

The purpose of this study was to determine the efficacy of adenovirus- based p53 gene therapy in the treatment of ovarian cancer using an intraperitoneal microscopic tumor animal model system. Adenovirus-mediated wild-type p53 gene was introduced into the NIH:OVCAR-3 human ovarian cancer cell line in vitro and in vivo. In order to study microscopic intraperitoneal tumor, athymic nude mice were inoculated intraperitoneally (i.p.) with 1 x 10⁷ OVCAR-3 cells and observed for tumor growth. Three days after inoculation with OVCAR-3 cells, the mice were divided into 3 treatment groups. One group received three daily i.p. injections of 1 x 10⁸ pfu Ad- CMV-p53, a second group received three daily i.p. injection of 1 x 10⁸ pfu of the control adenovirus construct expressing β galactosidase (Ad-CMV- βgal) and a third group received three daily i.p. injections of normal saline. Adenovirus-mediated introduction of the wild-type p53 gene in the ovarian cancer cell line resulted in transient high levels of p53 protein for 24-48 h. Cell cycle analysis revealed G1 arrest, as well as the appearance of apoptosis. In vitro cell growth assays showed growth inhibition of cancer cells infected with Ad-CMV-p53 compared to cells infected with Ad-CMV-βgal or normal saline. There was a significant increase in survival in the Ad-CMV- p53 adenovirus treated animals compared to the PBS treated animals (P = 0.004). Likewise, the survival in Ad-CMV-p53 treated mice was also significantly greater than mice treated with Ad-CMV-βgal (P < 0.0001). These results demonstrated that Ad-CMV-p53 treatment is effective in inhibiting tumor growth and prolonging survival in this microscopic cancer xenograft model. The results of this study constitute a step in translating promising in vitro and in vivo data from an adenovirus-based gene therapeutic model system into practical and scientifically based human cancer therapeutic trials.