Vogus Douglas R, Pusuluri Anusha, Chen Renwei, Mitragotri Samir
Dept. of Chemical Engineering University of California Santa Barbara, Santa Barbara CA 93106.
John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge MA 02138.
Bioeng Transl Med. 2018 Jan 19;3(1):49-57. doi: 10.1002/btm2.10082. eCollection 2018 Jan.
Combination chemotherapy is commonly used to treat late stage cancer; however, treatment is often limited by systemic toxicity. Optimizing drug ratio and schedule can improve drug combination activity and reduce dose to lower toxicity. Here, we identify gemcitabine (GEM) and doxorubicin (DOX) as a synergistic drug pair in vitro for the triple negative breast cancer cell line MDA-MB-231. Drug synergy and caspase activity were increased the most by exposing cells to GEM prior to DOX in vitro. While the combination was more effective than the single drugs at inhibiting MDA-MB-231 growth in vivo, the clear schedule dependence observed in vitro was not observed in vivo. Differences in drug exposure and cellular behavior in vivo compared to in vitro are likely responsible. This study emphasizes the importance in understanding how schedule impacts drug synergy and the need to develop more advanced strategies to translate synergy to the clinic.
联合化疗常用于治疗晚期癌症；然而，治疗常常受到全身毒性的限制。优化药物比例和给药方案可以提高联合用药活性并降低剂量以减少毒性。在此，我们确定吉西他滨（GEM）和阿霉素（DOX）在体外对三阴性乳腺癌细胞系MDA-MB-231是一对协同药物。在体外，先将细胞暴露于GEM再给予DOX时，药物协同作用和半胱天冬酶活性增加最为显著。虽然联合用药在体内抑制MDA-MB-231生长方面比单一药物更有效，但在体内未观察到体外明显的给药方案依赖性。与体外相比，体内药物暴露和细胞行为的差异可能是原因所在。本研究强调了理解给药方案如何影响药物协同作用的重要性，以及开发更先进策略将协同作用转化至临床的必要性。
