In Vivo Study Of Intraperitoneal Therapy With Topotecan On Serous Ovarian Cancer

Objectives: Conventionally intravenous treatment with topotecan has efficacy at least equivalent to paclitaxel manifested by a higher response rate and longer time to progression in patients with recurrent epithelial ovarian cancer and it has shown cytotoxic activity in patients refractory to platinum and paclitaxel. However, serious complications have limit its widely use. The aim of this study is to explore the therapeutic profile and availibity of topotecan given intraperitoneally in human ovarian cancer xenografted into athymic nude mice. It is also to be studied whether and how topotecan inhibits the neovascularization of ovarian cancer. Part Ⅰ: Experimental study on the effects of intraperitoneal therapy with topotecan on serous ovarian cancer 1. Effects of intraperitoneal therapy with topotecan on human serous ovarian cancer transplanted intraomensentarily in nude mice Methods: SKOV3ipl, a human serous ovarian cancer cell line previously grown subcutaneously was implanted intramesentarily as intact tissue into the female BALB/c(nu/nu) mice (6-8 weeks). Eighty mice were randomized assigned into eight groups (n=10). Onset of intraperitoneal treatment with either topotecan or cisplatin was on day 7. Animals scheduled for topotecan i.p. received intraperitoneal application of topotecan (1.5mg/kg×2, 3.0mg/kg×2, 6.0mg/kg×2 or 10.0mg/kg×1). Animals scheduled for topotecan i.v. received intravenous administration of topotecan (6.0mg/kg×2 or 10.0mg/kg×1). Two weeks after drug application animals were sacrificed. Tumor growth inhibition were assessed and compared with untreated mice and cisplatin intraperitoneally administered mice. Cell cycle division and cell apoptosis after drug administration were determined by flow cytometric 3拓扑替康腹腔化疗治疗浆液性卵巢癌的实验研究 复旦大学博士论文 英文摘要analysis. Results: Topotecan was more effective than cisplatin in vivo with route-dependent and dose-dependent tendancy. Intraperitoneal topotecan was significantly more effective than intravenous administration (P<0.05). Topotecan scheduled with 10.0 mg/kg/day i.p. was an optimal and well tolerated treatment with an inhibition rate of about 70.4%, which was significantly higher than those scheduled with topotecan 1.5mg/kg ×2, 3.0mg/kg ×2 or 6.0mg/kg ×2 (P<0.05). Topotecan played important role on each phase of cell cycle and induced apparent cell apoptosis, which was dose-dependent. 2. Effects of intraperitoneal therapy with topotecan on human serous ovarian cancer transplanted orthotopically in nude mice Methods: SKOV3ipl, a human ovarian tumor line previously grown subcutaneously was implanted orthotopically as intact tissue into the ovarian capsule of 98 BALB/c(nu/nu) mice (6-8 weeks) which were randomized assigned into six groups. Onset of treatment was on day 7. Animals scheduled for topotecan i.p. received intraperitoneal application of topotecan (5.0mg/kg×2 or 10.0mg/kg×1, n=14). Animals scheduled for topotecan i.v. received intravenous administration of topotecan (5.0mg/kg×2 or 10.0mg/kg×1, n=14). Two weeks after drug application half of animals were sacrificed. Tumor growth inhibition were assessed and compared with untreated mice (1n/2=14) and cisplatin intraperitoneally administered mice (1n/2=7). The other half numbers of animals in each group were followed up until their natural end points. Results: Intraperitoneal topotecan was significantly more effective than intravenous administration. Topotecan 10.0 mg/kg/day i.p. schedule was an optimal treatment for ovarian cancer with an inhibition rate of 66.2%. Under such schedule mice were well tolerated with milder metastasis and a longer mean survival period (64 days), which showed statistically significant difference toward any other treatment group (P<0.05). 4拓扑替康腹腔化疗治疗浆液性卵巢癌的实验研究 复旦大学博士论文 英文摘要Part Ⅱ : Experimental study of the anti-angio...