Optimizing Pemetrexed-Gemcitabine Combination in Patients with Advanced Non-small Cell Lung Cancer A Pharmacogenetic Approach

Introduction: The pemetrexed-gemcitabine combination is effective in patients with non-small cell lung cancer (NSCLC). Preclinical data suggest that pemetrexed may synergistically interact with gemcitabine by enhancing the expression of human equilibrative nucleoside transporter 1 (hENT1) and deoxycytidine kinase (dCK), increasing the uptake and intracellular activation of gemcitabine. A pharmacogenetic approach was adopted to evaluate hENT1 and dCK expressions in humans and to identify the potential best time interval to administer gemcitabine after pemetrexed in patients with advanced NSCLC. Methods: The dCK and hENT1 expressions, examined by quantitative real-time polymerase chain reaction, were analyzed during each cycle before and at 1, 2, 4, 6, 24, and 48 hours after pemetrexed administration. The relative differences from baseline to each planned time, for peak values and for the relative difference at peak, were measured. Results: Nineteen patients were treated with pemetrexed single agent (500 mg/m(2) every 15 or 21 days). Quantitative real-time polymerase chain reaction analysis revealed a statistically significant (p < 0.001) biphasic increase in both hENT1 and dCK genes at 1 to 2 and 24 to 48 hours after pemetrexed administration. Conclusions: This is the first evidence of dCK and hENT1 induction by pemetrexed in humans, suggesting that the pemetrexed -> gemcitabine combination should be optimized by the administration of gemcitabine 1 to 2 or 24 to 48 hours after pemetrexed. These results support further studies to validate the role of dCK/hENT1 in vivo modulation for the optimization of gemcitabine-pemetrexed combination in patients with NSCLC.