Human epithelial ovarian cancer xenotransplants into nude mice can be cured by adenovirus-mediated thymidine kinase gene therapy

Background: Adenovirus-mediated suicide gene therapy of ovarian cancer has effective anti-tumor effects in vitro and in vivo. By transduction of ovarian adenocarcinoma with the Herpes Simplex Thymidine Kinase gene and subsequent treatment with the antiviral agent ganciclovir, prolongation of survival has been described in nude mice. So far, however in animal models of solid tumors no cures have been reported after gene therapy. Methods: In a prospective randomized experimental design 76 mice with xenotransplanted serous ovarian carcinoma were treated with three different doses of ADV/RSV-TK at three different time points followed by intraperitoneal ganciclovir administration. The experiment was designed to show significance of survival differences upon doubling of the number of survived days at a p-value of 0.05 with a power of 80%. The endpoint of the trial was survival. Results: Treatment response was seen in all treated animals evident by significant prolongation of survival. Treatment response was dependent on the therapeutic viral dose and the tumor burden of the animal at the time of treatment. Two out of eight mice with early disease have now survived ten months without evidence of disease with untreated animals dying after nineteen days. Subcutaneous tumor development at the injection site was the reason of death in the remaining six mice of this group. Conclusion: Intraperitoneal ADV/RSV-TK suicide gene therapy of epithelial ovarian cancer in combination with ganciclovir administration can cure nude mice with early disease. This treatment modality may lend itself to incorporation into the current treatment concept of human ovarian malignancy. Clinical trials are warranted.