TY - JOUR
T1 - In vitro anti-mesothelioma activity of cisplatin-gemcitabine combinations
T2 - Evidence for sequence-dependent effects
AU - Zanellato, Ilaria
AU - Boidi, Carla Doriana
AU - Lingua, Guido
AU - Betta, Pier Giacomo
AU - Orecchia, Sara
AU - Monti, Elena
AU - Osella, Domenico
PY - 2011/2
Y1 - 2011/2
N2 - 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.
AB - 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.
KW - Cisplatin
KW - Combination chemotherapy
KW - Gemcitabine
KW - Malignant pleural mesothelioma
UR - http://www.scopus.com/inward/record.url?scp=79953800571&partnerID=8YFLogxK
U2 - 10.1007/s00280-010-1314-0
DO - 10.1007/s00280-010-1314-0
M3 - Article
SN - 0344-5704
VL - 67
SP - 265
EP - 273
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -
