Induction of gemcitabine (GCB)-related genes by pemetrexed (MTA): Assessment of the best time interval between MTA and GCB administration

Abstract

14145 Background: Both MTA and GCB are active drugs in non-small cell lung cancer (NSCLC). Many molecular events induced by MTA support the synergic interaction between the two drugs and explain why the sequence MTA ? GCB is more active than GCB ? MTA. Of major interest, MTA induces the expression of deoxycytidine kinase (dCK), the rate-limiting enzyme of GCB activation, and of the human equilibrative nucleoside transporter-1 (hENT1), the key transporter for the intracellular penetration of GCB. Even if the optimal sequence is well established, no information on the best administration time between the two drugs is available. Methods: To evaluate if there is a reproducible timing of maximum dCK and hENT1 expression by MTA, we measured these targets in patients with advanced NSCLC after administration of MTA 500 mg/m2 q2wks. All patients were not pre-treated with MTA or GCB. Gene-expression was measured in normal lymphocytes by quantitative real-time PCR (qRT-PCR), at various interval (up to 48 hrs) at each of the first 3 chemotherapy cycles. Results: Between September and December 2006, 8 out of the 19 planned patients were enrolled in the present study. At the time of this analysis, dosages from 63 samples / 9 cycles of chemotherapy are available. In all treatment cycles, qRT-PCR analysis revealed an increase of hENT1 and/or dCK genes at least in one time-point. With respect to gene expression levels at basal time, dCK increased both early (+1h: 3 out of 9 valuable cycles; + 4–6 hrs: 4 out of 9 cycles) and late (+ 24–48 hrs: 5 out of 9 cycles); hENT1 increased poorly at +1h (1 out of 6 valuable cycles) but consistently at + 4–6 hrs (5 out of 6 cycles) and late (+24–48 hrs: 6 out of 6 cycles). The increase of dCK and hENT1 gene expression was from + 15% to 285% and from 21% to + 380%, respectively. Conclusions: MTA induces GCB- related genes both at early and late time points with an inter-patients variability. The most rationale time interval between the two drugs administration will be valuated at the completion of the study. No significant financial relationships to disclose.