In vitro anti-mesothelioma activity of cisplatin-gemcitabine combinations: Evidence for sequence-dependent effects

Purpose: The present study addresses the optimization of gemcitabine-cisplatin protocols currently adopted in the clinical management of malignant pleural mesothelioma (MPM), using cell lines derived from different histological subtypes of MPM as an in vitro model. Methods: MPM cell lines were exposed either to single drugs or to their combinations, using a fixed dose ratio. Possible mechanisms for synergistic interactions were investigated by cell cycle analysis, western blot analysis of p53 phosphorylation status, and neutral comet assay to detect double strand breaks. Results: Four-hour pre-treatment with gemcitabine followed by 68-h exposure to cisplatin was found to exert synergistic activity in both epithelioid and sarcomatoid MPM subtypes, inducing a strong S-phase arrest that correlated with accumulation of double-strand breaks (DSBs). Conclusion The antiproliferative effects of the gemcitabine/cisplatin combination in mesothelioma cells can be maximized by pre-treatment with gemcitabine, suggesting that this drug increases cisplatin-induced DSBs by inhibiting DNA adduct repair.