Effect Of A Topoisomerase-1 Inhibitor (Topotecan) On The Efficacy Of Cisplatin In In Vitro And In Vivo Platinum-Resistant Ovarian Cancer Models

e13160 Background: Topotecan, a novel topoisomerase-1 inhibitor, is one of the drugs that might be effective against platinum-resistant epithelial ovarian cancer. However, the molecular mechanisms by which topotecan treatment inhibits cancer cell proliferation are unclear. The PI3K/Akt cascade is known to be an important survival factor in the signal transduction cascades involved in the cell growth. We investigated whether topotecan increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models. Methods: Mice: BALB/c Slc-nu/nu. Caov-3 cells: The cells are cisplatin-resistant human-derived ovarian cancer cell (mucinous adenocarcinoma). 5×106 Caov-3 cells were injected i.p. into 6-week-old female athymic nude mice (n=20). Athymic nude mice were injected i.p.with Caov-3 cells. Two weeks after inoculation, athymic nude mice inoculated i.p. with Caov-3 cells were randomized into four groups treated with the following for 6 weeks: (a) vehicle (PBS) alone; (b) CDDP (cisplatin 5 mg/kg) once a week; (c) TPT (topotecan 12.5 mg/kg) once a week; (d) CDDP + TPT (cisplatin 5mg/kg + topotecan 12.5 mg/kg) once a week. Results: Topotecan significantly inhibited the cisplatin-induced Akt activation in Caov-3 cells, but not in A2780 cells. In the presence of topotecan, cisplatin-induced inhibition and apoptosis was significantly enhanced in Caov-3 cells. Moreover, treatment with topotecan increased the efficacy of the cisplatin-induced inhibition in the intraabdominal dissemination and production of ascites in athymic nude mice inoculated i.p. with Caov-3 cells. Topotecan inhibited not only the cisplatin-induced Akt activity but also VEGF transcriptional activation and HIF-1a expression which was induced by cisplatin. Conclusions: These results suggest that combination therapy by cisplatin and topotecan would increase the therapeutic efficacy of the platinum-resistant epithelial ovarian cancer. No significant financial relationships to disclose.