RRC ID 43396
著者 Nagai S, Takenaka K, Sonobe M, Wada H, Tanaka F.
タイトル Schedule-dependent synergistic effect of pemetrexed combined with gemcitabine against malignant pleural mesothelioma and non-small cell lung cancer cell lines.
ジャーナル Chemotherapy
Abstract 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.
巻・号 54(3)
ページ 166-75
公開日 2008-1-1
DOI 10.1159/000140360
PII 000140360
PMID 18560222
MeSH Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / metabolism Carcinoma, Non-Small-Cell Lung / pathology* Cell Cycle / drug effects Cell Line, Tumor Deoxycytidine / analogs & derivatives* Deoxycytidine / pharmacology Drug Synergism Gemcitabine Gene Expression Regulation, Neoplastic / drug effects Gene Expression Regulation, Neoplastic / genetics Glutamates / pharmacology* Guanine / analogs & derivatives* Guanine / pharmacology Humans Lung Neoplasms / genetics Lung Neoplasms / metabolism Lung Neoplasms / pathology* Mesothelioma / genetics Mesothelioma / metabolism Mesothelioma / pathology* Pemetrexed Peptide Synthases / genetics Peptide Synthases / metabolism Pleural Neoplasms / genetics Pleural Neoplasms / metabolism Pleural Neoplasms / pathology* RNA, Messenger / genetics Reduced Folate Carrier Protein / genetics Thymidylate Synthase / genetics Thymidylate Synthase / metabolism Time Factors
IF 1.641
引用数 19
WOS 分野 PHARMACOLOGY & PHARMACY ONCOLOGY
リソース情報
ヒト・動物細胞 A549(RCB0098)