title: The pharmacological advantage of prolonged dose rate gemcitabine is restricted to patients with variant alleles of cytidine deaminase c.79A>C.
abstract: OBJECTIVE
  Controversy exists over the optimal dosing for the nucleoside analogue gemcitabine. A pharmacological advantage is achieved by prolonging infusion times but evidence for a clinical benefit has been conflicting. We hypothesized that polymorphisms in genes involved in gemcitabine accumulation, particularly the cytidine deaminase CDA c.79A>C, may influence the optimal dosing regimen in individual patients.
  
  
  METHODS
  DNA was collected from 32 patients participating in a randomized crossover study comparing 30-min with 100-min infusions of gemcitabine. The relationships between seven polymorphisms among three genes (CDA, RRM1 and DCK) and (i) gemcitabine triphosphate accumulation; (ii) gemcitabine-induced toxicity; and (iii) dose delivery were examined for each infusion time and week of administration.
  
  
  RESULTS
  There were trends for increased accumulation of gemcitabine-triphosphate (GEM-TP) with the variant alleles of CDA c.79A>C, and RRM1-37C>A and -524T>C but none of these reached statistical significance in a univariate analysis. In a multivariable model there were significant effects of infusion duration and week of administration on GEM-TP accumulation. There were significant interactions between CDA c.79A>C (P=0.01) and RRM1-37C>A (P=0.019) genotypes, infusion time, and arm. More patients with one or two CDA c.79 variant alleles had doses delays (57 vs 13 %, P=0.03) and a pharmacological advantage for prolonged infusion after week 1.
  
  
  CONCLUSIONS
  It is important to consider both pharmacokinetics and pharmacogenetics in optimizing gemcitabine accumulation. This represents a classical interaction between genes and environment and provides support for the consideration of both CDA genotype and infusion duration in development of an individualized dosing strategy.
authors.affiliation: Cancer Pharmacology Therapeutics Group Medical Oncology, St George and Sutherland Hospitals, Sydney, Australia.
authors.forename: Ekkaphon
authors.initials: E
authors.lastname: Metharom
authors.forename: Peter
authors.initials: P
authors.lastname: Galettis
authors.forename: Susan
authors.initials: S
authors.lastname: Manners
authors.forename: Maria
authors.initials: M
authors.lastname: Jelinek
authors.forename: Winston
authors.initials: W
authors.lastname: Liauw
authors.forename: Paul L
authors.initials: PL
authors.lastname: de Souza
authors.forename: Janelle M
authors.initials: JM
authors.lastname: Hoskins
authors.forename: Matthew
authors.initials: M
authors.lastname: Links
mesh_terms: D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003564:Cytidine Deaminase / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine