A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity.
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.
Yue
Lijie
L
Division of Cardiovascular Medicine, Vascular Medicine, Angiogenesis and Vascular Development, Department of Pediatrics, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Saikawa
Yutaka
Y
Ota
Kazuhisa
K
Tanaka
Motohiro
M
Nishimura
Ryosei
R
Uehara
Takahiro
T
Maeba
Hideaki
H
Ito
Takashi
T
Sasaki
Takuma
T
Koizumi
Shoichi
S
D002675:Child, Preschool; D003561:Cytarabine / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D003641:Deamination / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000235:genetics; D008826:Microbial Sensitivity Tests; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D016415:Sequence Alignment
D018076:DNA, Complementary; D011994:Recombinant Proteins; D003561:Cytarabine; D003564:Cytidine Deaminase