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Received for publication November 24, 2004.
Revised March 22, 2005.
Accepted for publication March 28, 2005.
Purpose. Gemcitabine and pemetrexed are effective agents in the treatment of non-small cell lung cancer (NSCLC) and the present study investigates cellular and genetic aspects of their interaction against A549, Calu-1 and Calu-6 cells. Cells were treated with pemetrexed and gemcitabine, and their interaction was assessed using the combination index. The role of drug metabolism on gemcitabine cytotoxicity was examined with inhibitors of deoxycytidine kinase (dCK), 5'-nucleotidase and cytidine deaminase, while the role of pemetrexed targets, thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT), on drug chemosensitivity was analysed in cytotoxicity rescue studies. The effect of gemcitabine and pemetrexed on Akt phosphorylation was investigated with ELISA, while quantitative PCR was used to study target gene expression profile and its modulation by each drug. Synergistic cytotoxicity was demonstrated and pemetrexed significantly decreased the amount of phosphorylated Akt, enhanced apoptosis and increased the expression of dCK in A549 and Calu-6 cells, as well as of the human nucleoside equilibrative transporter 1 (hENT1) in all cell lines. PCR demonstrated a correlation between dCK expression and gemcitabine sensitivity, while expression of TS, DHFR and GARFT was predictive of pemetrexed chemosensitivity. These data demonstrated that (1) gemcitabine and pemetrexed synergistically interact against NSCLC cells, through suppression of Akt phosphorylation and induction of apoptosis; (2) gene expression profile of critical genes may predict for drug chemosensitivity, and (3) pemetrexed enhances dCK and hENT1 expression thus suggesting the role of gene expression modulation for rational development of chemotherapy combinations.
Key words:
Mechanisms of cell killing/apoptosis, Nucleoside/Nucleotide derivatives
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