Kieback Dirk G, Fischer Dagmar-Christiane, Engehausen Dirk G, Sauerbrei Willi, Oehler Martin K, Tong Xiao-Wen, Aguilar-Cordova Estuardo
Department of Obstetrics and Gynecology, Freiburg University Medical Center, Freiburg, Germany.
Cancer Gene Ther. 2002 May;9(5):478-81. doi: 10.1038/sj.cgt.7700462.
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 or 8 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.
使用人卵巢癌小鼠模型来研究腺病毒介导的胸苷激酶基因治疗（gt）与化疗联合的效果。160只雌性CD-1裸鼠经腹腔注射Ov-ca-2774细胞。拓扑替康（6或12mg/kg）或紫杉醇（18或36mg/kg）的腹腔治疗在第4天或第8天开始，并在4天后重复一次。计划接受gt治疗的动物在化疗前1天经腹腔应用腺病毒/呼吸道合胞病毒胸苷激酶（adv/rsv-tk），随后用更昔洛韦（gcv；10mg/kg，每12小时一次，共6天）治疗。选择生存作为研究终点。虽然肿瘤负荷对生存几乎没有影响，但较低剂量的两种细胞毒性药物都比高剂量更有效。在拓扑替康组中，拓扑替康与gt之间存在相互作用。仅用低剂量拓扑替康治疗的动物生存最佳，添加gt显著缩短了生存时间。使用高剂量时，gt不影响生存时间。对于紫杉醇，仅观察到gt对生存时间有轻微影响。由于治疗毒性，该动物模型可能不利于评估gt与化疗的联合效果。剂量的影响随时间变化很大。接受高剂量化疗的小鼠在用药后的时间段内死亡风险大幅增加，而低剂量的这一优势在后期消失。
