Combination effects of TAS-103, a novel dual topoisomerase I and II inhibitor, with other anticancer agents on human small cell lung cancer cells

Purpose: TAS-103 [6-((2-(dimethylamino) ethyl)amino)-3-hydroxy-7H-indeno(2, 1-c)quinolin-7-one dihydrochloride] is a newly synthesized dual inhibitor of topoisomerase I and II. Since anticancer drugs are used in combination w ith other drugs for effective chemotherapy, we investigated the cytotoxic e ffect of TAS-103 in combination with other conventional anticancer agents, such as cisplatin, vindesine, doxorubicin, 5-fluorouracil. and the antitopo isomerase inhibitors SN-38 and etoposide in vitro. Methods: Inhibition of t he growth of the human small-cell lung cancer cell line SBC-3 was evaluated using the tetrazolium dye (MTI) assay. Drug interactions were evaluated by isobologram analysis and the determination of combination indices suppleme nted by a three-dimensional model. Results: Simultaneous use of TAS-103 and cisplatin had a supradditive effect, but combinations of TAS-103 with othe r drugs had an additive or marginally subadditive effect. Three-dimensional model analysis added more information about the synergistic concentration ranges of two drugs (cisplatin 200-400 nM and TAS-103 7-10 nM). Sequential use of TAS-103 and cisplatin had only an additive effect. Conclusions: Thes e results suggest that the concomitant use of TAS-103 and cisplatin has a g reater cytotoxic effect on cancer cells than single drug use, and may provi de a beneficial effect in the treatment of small-cell lung cancer.