A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity

Pharmacogenetics. 2003 Jan;13(1):29-38. doi: 10.1097/00008571-200301000-00005.

Abstract

To test the hypothesis that analyses of drug targets for polymorphism will help to establish gene-based information for the treatment of cancer patients, we investigated the functional single-nucleotide polymorphisms in the human cytidine deaminase (HDCA) gene. The cDNAs from 52 leukaemia/lymphoma samples and 169 control blood samples were direct-sequenced and analysed for the polymorphisms. Three different polymorphisms (A79C, G208A and T435C) were identified in the coding region of the HDCA gene and displayed allelic frequencies of 20.1%, 4.3% and 70.1%, respectively. No association with susceptibility to disease was observed. A novel polymorphism, G208A produced an alanine to threonine substitution (A70T) within the conserved catalytic domain. By introduction of the polymorphic HCDA genes into the yeast CDA-null mutants, the HCDA-70T showed 40% and 32% activity of prototype for cytidine and ara-C substrates, respectively (P < 0.01). The ara-C IC50 value of the yeast transformants carrying HCDA-70T was 757 +/- 33 micromol and was significantly lower (P < 0.01) than that of prototype (941 +/- 58 micromol). This study demonstrated a population characterized with 208A genotype for, which potentially leads one more sensitive to ara-C treatment than prototype. Accumulation of polymorphisms in the genes responsible for drug metabolism and determination of polymorphism-induced biological variations could provide the additional therapeutic strategies in risk-stratified protocols for the treatment of childhood malignancies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • Cytarabine / pharmacology*
  • Cytidine Deaminase / biosynthesis
  • Cytidine Deaminase / chemistry
  • Cytidine Deaminase / genetics*
  • DNA, Complementary / genetics
  • Deamination / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leukemia / genetics
  • Microbial Sensitivity Tests
  • Polymorphism, Single Nucleotide*
  • Recombinant Proteins / chemistry
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / genetics
  • Sequence Alignment

Substances

  • DNA, Complementary
  • Recombinant Proteins
  • Cytarabine
  • Cytidine Deaminase