Intraperitoneal adenovirus-mediated suicide gene therapy in combination with either topotecan or paclitaxel in nude mice with human ovarian cancer

Abstract

A mouse model of human ovarian cancer was used to investigate the effect of adenovirus-mediated thymidine kinase gene therapy (gt) in combination with chemotherapy. One hundred sixty female CD-1 nu/nu mice were injected intraperitoneally with Ov-ca-2774 cells. Onset of intraperitoneal treatment with either topotecan (6 or 12 mg/kg) or paclitaxel (18 or 36 mg/kg) was on day 4 or8 and was repeated once after 4 days. Animals scheduled for gt received intraperitoneal application of adv/rsv-tk 1 day prior to chemotherapy and were subsequently treated with ganciclovir (gcv; 10 mg/kg, every 12 hours for 6 days). Survival was chosen as study endpoint. Whereas tumor burden had hardly any effect on survival, the lower dose of either cytotoxic agent was seen to be more effective than the higher one. In the topotecan group, an interaction between topotecan and gt was present. Survival was best for animals treated with low dose of topotecan only, the addition of gt reduced survival time significantly. With the higher dose, gt did not affect survival time. With paclitaxel, only slight effects of gt on the survival times were seen. Due to treatment toxicity, this animal model may be problematic for the evaluation of gt and chemotherapy combinations. The effect of dose varied strongly with time. Mice treated with high-dose chemotherapy had a substantially increased risk of dying in the time period following application, whereas this advantage of the lower dose disappeared later.