Efficacy and toxicity of adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene followed by administration of ganciclovir were studied in vivo. A human epithelial ovarian cancer animal model was established in nude mice using the serous ovarian adenocarcinoma cell line Ov-ca-2774. Intraperitoneal (ip) injection of 1 x 10(8) Ov-ca-2774 cells resulted in tumor growth and formation of malignant ascites in all 15 animals. In a prospective randomized experimental design mice were treated 1, 3, or 7 days after ip injection of 1 x 10(8) cells with ip injection of 2 x 10(8), 6.7 x 10(8), or 2 x 10(9) pfu ADV.RSV-TK followed by administration of ganciclovir (10 microgram /ml, ip, bid) for 6 consecutive days. End points were survival and toxicity. Mice treated with GCV or HSV-TK alone died from 14.4 +/- 1.7 to 19.5 +/- 3.5 days after treatment as did untreated controls. No toxicity of ADV.RSV-TK was found up to 2 x 10(9) pfu (2 x 10(11) particles). The mice with the highest tumor burden treated with the lowest viral dose lived significantly longer than controls (P <0.05). Median survival in all other groups of mice treated with ADV.RSV-TK plus GCV was even longer (P <0.01). Treatment benefit was dependent on ADV/RSV-TK dose and tumor burden. Adenovirus-mediated thymidine kinase gene therapy is a realistic approach to ovarian cancer treatment that warrants investigation in the clinical setting.
