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

Lijie Yue, Yutaka Saikawa, Kazuhisa Ota, Motohiro Tanaka, Ryosei Nishimura, Takahiro Uehara, Hideaki Maeba, Takashi Ito, Takuma Sasaki, Shoichi Koizumi

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101 Citations (Scopus)

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 (HCDA) 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 HCDA 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 μmol and was significantly lower (P<0.01) than that of prototype (941 ± 58 μmol). This study demonstrated a population characterized with 208A genotype for HCDA, 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. Pharmacogenetics 13:29-38

Original languageEnglish
Pages (from-to)29-38
Number of pages10
JournalPharmacogenetics
Volume13
Issue number1
DOIs
Publication statusPublished - Jan 2003

All Science Journal Classification (ASJC) codes

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

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