BACKGROUND: Pemetrexed, a multi-targeted antifolate (MTA), is a promising agent in the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). With the aim of finding an optimal schedule for the combination therapy of MTA and gemcitabine (GEM), we investigated their interaction against an MPM cell line, 211H, and the NSCLC cell lines A549 and H1299. METHODS: Combination index analysis was used in 3 different schedules. Cell cycle analysis by flow cytometry and real-time RT-PCR analysis of thymidylate synthase (TS), folylpolyglutamate synthetase (FPGS) and reduced folate carrier 1 (RFC1) genes were performed to understand the biological consequences of their interaction. RESULTS: MTA showed potent cytotoxicity against 211H cells (IC(50), 67 nM for 48 h exposure), compared to NSCLC cell lines. Significantly higher expression of FPGS and RFC1 mRNAs in 211H cells were associated with MTA sensitivity. Simultaneous exposure of MTA and GEM was antagonistic in all cell lines tested. Strong synergism was observed in 211H cells when MTA preceded GEM, but the inverted sequence showed antagonism. Similar results were exhibited in H1299 cells, whereas a moderately synergistic effect was observed in A549 cells when GEM preceded MTA. S phase accumulation by MTA treatment partly supported these results. CONCLUSION: Sequential administration of MTA and GEM is active, and the schedule of MTA followed by GEM is recommended for treating MPM. (c) 2008 S. Karger AG, Basel.
BACKGROUND:Pemetrexed, a multi-targeted antifolate (MTA), is a promising agent in the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). With the aim of finding an optimal schedule for the combination therapy of MTA and gemcitabine (GEM), we investigated their interaction against an MPM cell line, 211H, and the NSCLC cell lines A549 and H1299. METHODS: Combination index analysis was used in 3 different schedules. Cell cycle analysis by flow cytometry and real-time RT-PCR analysis of thymidylate synthase (TS), folylpolyglutamate synthetase (FPGS) and reduced folate carrier 1 (RFC1) genes were performed to understand the biological consequences of their interaction. RESULTS: MTA showed potent cytotoxicity against 211H cells (IC(50), 67 nM for 48 h exposure), compared to NSCLC cell lines. Significantly higher expression of FPGS and RFC1 mRNAs in 211H cells were associated with MTA sensitivity. Simultaneous exposure of MTA and GEM was antagonistic in all cell lines tested. Strong synergism was observed in 211H cells when MTA preceded GEM, but the inverted sequence showed antagonism. Similar results were exhibited in H1299 cells, whereas a moderately synergistic effect was observed in A549 cells when GEM preceded MTA. S phase accumulation by MTA treatment partly supported these results. CONCLUSION: Sequential administration of MTA and GEM is active, and the schedule of MTA followed by GEM is recommended for treating MPM. (c) 2008 S. Karger AG, Basel.
Authors: An Wouters; Bea Pauwels; Filip Lardon; Greet G O Pattyn; Hilde A J Lambrechts; Marc Baay; Paul Meijnders; Jan B Vermorken Journal: BMC Cancer Date: 2010-08-19 Impact factor: 4.430
Authors: Darya Karatkevich; Haibin Deng; Yanyun Gao; Emilio Flint; Ren-Wang Peng; Ralph Alexander Schmid; Patrick Dorn; Thomas Michael Marti Journal: Int J Mol Sci Date: 2022-10-08 Impact factor: 6.208
Authors: J E Nutt; A R A Razak; K O'Toole; F Black; A E Quinn; A H Calvert; E R Plummer; J Lunec Journal: Br J Cancer Date: 2010-01-05 Impact factor: 7.640