title: Optimal combination of gemcitabine, sorafenib, and S-1 shows increased efficacy in treating cholangiocarcinoma in vitro and in vivo.
abstract: 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+0.084A+109B+6.06C+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.
authors.affiliation: aDepartment of General Surgery, Shanghai Jiao Tong University Affiliated First People's Hospital bDepartment of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital cSchool of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Zhengyun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zunqiang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Xianting
authors.initials: X
authors.lastname: Ding
authors.forename: Guangwen
authors.initials: G
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001650:Bile Duct Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015233:Models, Statistical; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010094:Oxonic Acid / Q000008:administration & dosage; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011897:Random Allocation; D000077157:Sorafenib; D005641:Tegafur / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D004338:Drug Combinations; D010671:Phenylurea Compounds; D003841:Deoxycytidine; C079198:S 1 (combination); D005641:Tegafur; D009536:Niacinamide; D010094:Oxonic Acid; D000077157:Sorafenib; D000093542:Gemcitabine