Schedule dependent synergy of gemcitabine and doxorubicin: Improvement of in vitro efficacy and lack of in vitro-in vivo correlation

Douglas R Vogus; Anusha Pusuluri; Renwei Chen; Samir Mitragotri

doi:10.1002/btm2.10082

Schedule dependent synergy of gemcitabine and doxorubicin: Improvement of in vitro efficacy and lack of in vitro-in vivo correlation

Bioeng Transl Med. 2018 Jan 19;3(1):49-57. doi: 10.1002/btm2.10082. eCollection 2018 Jan.

Authors

Douglas R Vogus^{1

2}, Anusha Pusuluri^{1

2}, Renwei Chen³, Samir Mitragotri²

Affiliations

¹ Dept. of Chemical Engineering University of California Santa Barbara, Santa Barbara CA 93106.
² John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge MA 02138.
³ Center for Bioengineering University of California, Santa Barbara Santa Barbara CA 93106.

Abstract

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.

Keywords: combination chemotherapy; doxorubicin; gemcitabine; schedule; synergy.