Abstract
Abstract Introduction: Triple negative breast cancer (TNBC) is characterized by high proliferation and poor prognosis compared to other types of breast cancer. Treatment for TNBC needs to be improved because TNBC cells have no estrogen, progesterone and HER2 receptor, and approach for cure of TNBC is limited. TNBC patients with BRCA mutation have sensitivity to olaparib, a PARP inhibitor, inhibiting DNA repair. Therefore, treatment based on olaparib may be more effective for TNBC with BRCA mutation. In this study, we examined antitumor effects of olaparib to TNBC cells and combined effects with cytotoxic agents that could potentiate the antitumor effect of olaparib. Methods: Sensitivity of olaparib to TNBC cell lines was examined by cell growth inhibition assay using CCK-8 kit and the combined antitumor effect with cytotoxic agents was evaluated by combination index. Intracellular poly (ADP-ribosyl) ation in MDA-MB-436 (MM436) cells was assessed by western blotting. Olaparib (50 mg/kg) and CPT-11 (15 and 30 mg/kg) were administered to Balb/c nude mice inoculated MM436 cells subcutaneously. The drug concentrations in plasma and tissues were measured by LC-MS/MS system (QTRAP5500, AB SCIEX). Results: Inhibitory effect of cell growth by olaparib was 20-fold higher at a maximum in MM436 cells with BRCA mutation compared to other TNBC cell lines. Combination index of olaparib with CPT-11 in MM436 cells was lowest. In addition, CPT-11 caused Poly (ADP-ribosyl) ation higher than other cytotoxic agents in MM436 cells. In animal model, tumor growth was more inhibited by co-administration of olaparib and CPT-11 than olaparib or CPT-11 alone. Plasma concentration of these drugs and active metabolite SN-38 in any time period tended to be higher in co-administered animals than single-administered animals. In addition, Tumor tissue concentration of SN-38 at 2 hours after administration was higher in a group of combined administration than that of single administration. Conclusion: The mechanisms of combined effect of olaparib and CPT-11 was that exposure of CPT-11 to TNBC cells with BRCA mutation caused PARP activation by its cytocidal action and synthetic lethality of olaparib worked more effectively. Furthermore, drug-drug interaction between olaparib and CPT-11 caused inhibiting activity of transporter function such as P-gp or BCRP and tumor tissue exposure levels increased. Therefore, the alteration of pharmacokinetics and pharmacodynamics contributes to the effect of combined treatment. The present results supported that olaparib treatment for TNBC with BRCA mutation had a potential of clinical benefit in combination with CPT-11. Citation Format: Yuki Takashima, Jun Hashimoto, Yuka Kitamura, Shuichi Shimma, Yasuhiro Fujiwara, Fumiaki Koizumi, Kenji Tamura, Akinobu Hamada. Combined effects of olaparib and cytotoxic agents to triple negative breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1678. doi:10.1158/1538-7445.AM2014-1678
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