title: Variability in transport and biotransformation of cytarabine is associated with its toxicity in peripheral blood mononuclear cells.
abstract: OBJECTIVE
  To adopt an individualized approach to assess cytarabine (ara-C) hematotoxicity, we studied the relationship between pharmacogenetic variability in the cytidine deaminase gene (CDA) and ara-C toxicity in native peripheral blood mononuclear cells from 100 healthy volunteers.
  
  
  METHODS
  Peripheral blood mononuclear cells were incubated for 48 h with 3 µM ara-C, and cell viability was analyzed by flow cytometry with and without the addition of an equilibrative nucleoside transporter transport inhibitor. CDA promoter and exonic variants were genotyped to derive haplotypes for the CDA gene.
  
  
  RESULTS
  Significant between-subject variability was observed in ara-C toxicity (21-fold with 40.1% coefficient of variation compared with 1.2-fold within-subject variability [9.6% coefficient of variation]). Inhibition of hENT1 reversed ara-C cytotoxicity. The linked CDA promoter variants -451C>T, -92A>G, -31Del and the exonic 79A>C variant were associated with ara-C toxicity (p < 0.05). CDA*2A haplotype was associated with ara-C toxicity (p = 0.03).
  
  
  CONCLUSIONS
  Genetic polymorphisms within CDA may be risk factors for ara-C-induced hematotoxicity. Original submitted 6 October 2010; Revision submitted 29 November 2010.
authors.affiliation: Institute of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, Germany.
authors.forename: Sumit
authors.initials: S
authors.lastname: Parmar
authors.forename: Angela
authors.initials: A
authors.lastname: Seeringer
authors.forename: Dina
authors.initials: D
authors.lastname: Denich
authors.forename: Franziska
authors.initials: F
authors.lastname: Gärtner
authors.forename: Kai
authors.initials: K
authors.lastname: Pitterle
authors.forename: Tatiana
authors.initials: T
authors.lastname: Syrovets
authors.forename: Barbara
authors.initials: B
authors.lastname: Ohmle
authors.forename: Julia C
authors.initials: JC
authors.lastname: Stingl
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003561:Cytarabine / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003564:Cytidine Deaminase / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D003561:Cytarabine; D013868:Thioinosine; D003564:Cytidine Deaminase; C001789:4-nitrobenzylthioinosine