TY - JOUR
T1 - A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity
AU - Yue, Lijie
AU - Saikawa, Yutaka
AU - Ota, Kazuhisa
AU - Tanaka, Motohiro
AU - Nishimura, Ryosei
AU - Uehara, Takahiro
AU - Maeba, Hideaki
AU - Ito, Takashi
AU - Sasaki, Takuma
AU - Koizumi, Shoichi
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/1
Y1 - 2003/1
N2 - 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
AB - 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
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U2 - 10.1097/00008571-200301000-00005
DO - 10.1097/00008571-200301000-00005
M3 - Article
C2 - 12544510
AN - SCOPUS:0037245970
SN - 1744-6872
VL - 13
SP - 29
EP - 38
JO - Pharmacogenetics
JF - Pharmacogenetics
IS - 1
ER -
