title: Optimizing pemetrexed-gemcitabine combination in patients with advanced non-small cell lung cancer: a pharmacogenetic approach.
abstract: BACKGROUND
  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 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.
authors.affiliation: Unit of Medical Oncology of Respiratory Tract and Sarcomas, New Drugs Development Division, European Institute of Oncology, Milan, Italy. tommaso.de-pas@ieo.it
authors.forename: Tommaso M
authors.initials: TM
authors.lastname: De Pas
authors.forename: Francesca
authors.initials: F
authors.lastname: Toffalorio
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Davide
authors.initials: D
authors.lastname: Radice
authors.forename: Francesca
authors.initials: F
authors.lastname: Russo
authors.forename: Ilaria
authors.initials: I
authors.lastname: Angeli
authors.forename: Giulia
authors.initials: G
authors.lastname: Calamai
authors.forename: Gianluca
authors.initials: G
authors.lastname: Spitaleri
authors.forename: Chiara
authors.initials: C
authors.lastname: Catania
authors.forename: Cristina
authors.initials: C
authors.lastname: Noberasco
authors.forename: Alessandra
authors.initials: A
authors.lastname: Milani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Filippo
authors.initials: F
authors.lastname: De Braud
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003842:Deoxycytidine Kinase / Q000235:genetics*; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D000068437:Pemetrexed; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000093542:Gemcitabine
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D005971:Glutamates; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C438649:SLC29A1 protein, human; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine