title: Schedule-dependent synergistic interaction between gemcitabine and oxaliplatin in human gallbladder adenocarcinoma cell lines.
abstract: To define the most effective combination schedule of gemcitabine and oxaliplatin (L-OHP), we investigated the in-vitro interaction between these drugs in a panel of four human gallbladder adenocarcinoma cell lines (HAG-1, GB-d1, NOZ, and G-415). Cytotoxic activity was determined by the WST-1 assay. Different schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation and apoptosis were evaluated by flow cytometry. Simultaneous and sequential treatments of gemcitabine followed by L-OHP exhibited synergistic effects in all four cell lines, whereas the reverse sequence largely showed an antagonism. Gemcitabine exclusively arrested cells at the G0/G1 phase, and L-OHP at the G2/M phase, as measured by flow cytometric analyses. Apoptosis was most prominent when cells were treated simultaneously or in a sequence gemcitabine followed by L-OHP, producing apoptosis in treated cells (27-30%). In contrast, the reverse sequence yielded only 6-7% induction of apoptosis, the rate being not significantly different from those induced by each drug singly. Moreover, this sequence dependence was further confirmed by the experiment, which compared the number of HAG-1 cells 7 days after these combination schedules. These findings suggest that the interaction of gemcitabine and L-OHP is highly schedule dependent, with the most efficacious interaction observed in either simultaneous combination or in a sequence combination of gemcitabine followed by L-OHP.
authors.affiliation: First Department of Internal Medicine and Department of Biosystemic Science of Medicine, Graduate School of Medicine, Kyushu University, Maidashi, Higashi-Ku, Japan.
authors.forename: Akitaka
authors.initials: A
authors.lastname: Makiyama
authors.forename: Baoli
authors.initials: B
authors.lastname: Qin
authors.forename: Keita
authors.initials: K
authors.lastname: Uchino
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shibata
authors.forename: Shuji
authors.initials: S
authors.lastname: Arita
authors.forename: Taichi
authors.initials: T
authors.lastname: Isobe
authors.forename: Gen
authors.initials: G
authors.lastname: Hirano
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kusaba
authors.forename: Eishi
authors.initials: E
authors.lastname: Baba
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Shuji
authors.initials: S
authors.lastname: Nakano
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077150:Oxaliplatin; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000093542:Gemcitabine