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

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Abstract

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.

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Acknowledgments

We gratefully thank European Union (COST D39 action “Metallo-Drug Design and Action”), Regione Piemonte (CIPE project-code A 370 and Ricerca Sanitaria Finalizzata 2009), Associazione Sviluppo e Territorio (ATF, Alessandria) and “Metal in Life and Environment” Consortium (CIRCMSB, Bari) for financial support. Finally, we are indebted to the anonymous referees, whose criticisms and suggestions improved the quality of the manuscript.

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Authors and Affiliations

  1. Department of Environmental and Life Sciences, Università del Piemonte Orientale “Amedeo Avogadro”, Via T. Michel, 11, 15121, Alessandria, Italy

    Ilaria Zanellato, Carla Doriana Boidi, Guido Lingua & Domenico Osella

  2. Pathology Unit, Department of Oncology, Azienda Sanitaria Ospedaliera, Via Venezia 16, 15121, Alessandria, Italy

    Pier-Giacomo Betta & Sara Orecchia

  3. Department of Structural and Functional Biology, Section of Pharmacology, University of Insubria, Via A. da Giussano 12, 21052, Busto Arsizio, Italy

    Elena Monti

Authors
  1. Ilaria Zanellato
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  2. Carla Doriana Boidi
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  3. Guido Lingua
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  4. Pier-Giacomo Betta
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  5. Sara Orecchia
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  7. Domenico Osella
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Correspondence to Domenico Osella.

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Zanellato, I., Boidi, C.D., Lingua, G. et al. In vitro anti-mesothelioma activity of cisplatin–gemcitabine combinations: evidence for sequence-dependent effects. Cancer Chemother Pharmacol 67, 265–273 (2011). https://doi.org/10.1007/s00280-010-1314-0

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