Schedule-dependent synergistic effect of pemetrexed combined with gemcitabine against malignant pleural mesothelioma and non-small cell lung cancer cell lines.
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.


CONCLUSIONS
Sequential administration of MTA and GEM is active, and the schedule of MTA followed by GEM is recommended for treating MPM.
Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Shinjiro
S
Nagai
Kazumasa
K
Takenaka
Makoto
M
Sonobe
Hiromi
H
Wada
Fumihiro
F
Tanaka
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000068437:Pemetrexed; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D058978:Reduced Folate Carrier Protein / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D000093542:Gemcitabine
D005971:Glutamates; D012333:RNA, Messenger; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D013940:Thymidylate Synthase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D000093542:Gemcitabine