Optimal combination of gemcitabine, sorafenib, and S-1 shows increased efficacy in treating cholangiocarcinoma in vitro and in vivo.

Cholangiocarcinoma (CCA) is one of the most difficult cancers to treat and lacks an established standard chemotherapy regimen. This study evaluated the effects of different combinations of gemcitabine, sorafenib, and S-1 on CCA cells to identify the optimal drug combination. A fractional factorial design method was applied in drug combination experiments to determine the optimal combination of these three drugs (gemcitabine=1.4 mmol/l, sorafenib=0.03 mmol/l, S-1=0.185 mmol/l). We constructed a mathematical model with a small number of runs (Y=1.14-0.377A-23.0B-1.81C+0.084A2+109B2+6.06C2+3.83AB+0.175AC-40.4BC) to predict the efficacy of combinations of the drugs. The optimal combination can significantly inhibit the AKT/mTOR pathway, and thus CCA cell proliferation, and can induce cell apoptosis. In vivo, this combination (gemcitabine=1.4 mmol/l, sorafenib=0.03 mmol/l, S-1=0.185 mmol/l) can significantly inhibit tumor growth. The present study showed that the mathematical model was reliable and could predict the efficacy of the different drug combinations. The optimal combination of these drugs may aid the development of a promising standard chemotherapy regimen for CCA. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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