Molecular mechanism of in vitro pemetrexed sensitivity according to histological type in non-small cell lung cancer.

Abstract

e13090 Background: Pemetrexed (Alimta, ALM) is a new multitarget antifolate metabolite anticancer drug. Non-small cell lung cancer (NSCLC) is now treated with selective chemotherapy based on its classification as either non-squamous cell carcinoma or squamous cell carcinoma (SCC). This study was designed to investigate the relationship between in vitro chemosensitivity to ALM and both clinicopathological factors and the expressions of ALM-related enzymes and carrier molecule in NSCLC. Methods: Seventy NSCLC samples (56 adenocarcinoma and 14 SCC) were used. Chemosensitivity was assessed by the succinate dehydrogenase inhibition (SDI) test for three antimetabolic anticancer drugs, including ALM, 5-fluorouracil, gemcitabine. Samples showing more than the median of the succinate dehydrogenase (SD) activity, which reflects the cell viability, were defined as "Resistant" and samples showing less than the median were defined as "Sensitive." The mRNA expression levels of target enzymes of ALM (thymidylate synthase (TS), dihydrofolate reductase and glycinamide ribonucleotide formyltransferase), metabolic enzymes of ALM (γ-glutamyl hydrase (GGH) and folypolyglutamate synthase) and reduce folate carrier (RFC) were measured by reverse transcriptase polymerase chain reaction analysis to examine the influence on chemosensitivity to ALM. Results: Of 3 antimetabolic drugs, only ALM showed significant difference of chemosensitivity according to the histological type. SCC samples were more resistant to ALM than adenocarcinoma samples. In adenocarcinoma, no significant relationship between chemosensitivity to ALM and clinicopathological factors was observed. SCC samples showed higher expression of TS and lower expression of RFC than adenocarcinoma samples. In adenocarcinoma, only GGH was inversely correlated with chemosensitivity to ALM. Conclusions: The present study suggested that, in SCC, the expressions of TS and RFC were associated with the chemosensitivity to ALM. In adenocarcinoma, the expression of GGH was associated with the chemosensitivity to ALM.