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

研究成果: ジャーナルへの寄稿記事

100 引用 (Scopus)

抄録

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

元の言語英語
ページ(範囲)29-38
ページ数10
ジャーナルPharmacogenetics
13
発行部数1
DOI
出版物ステータス出版済み - 1 1 2003
外部発表Yes

Fingerprint

Cytidine Deaminase
Cytarabine
Single Nucleotide Polymorphism
Genes
Yeasts
Cytidine
Pharmacogenetics
Disease Susceptibility
Threonine
Clinical Protocols
Alanine
Pharmaceutical Preparations
Inhibitory Concentration 50
Lymphoma
Catalytic Domain
Neoplasms
Leukemia
Therapeutics
Complementary DNA
Genotype

All Science Journal Classification (ASJC) codes

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

これを引用

A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. / Yue, Lijie; Saikawa, Yutaka; Ota, Kazuhisa; Tanaka, Motohiro; Nishimura, Ryosei; Uehara, Takahiro; Maeba, Hideaki; Ito, Takashi; Sasaki, Takuma; Koizumi, Shoichi.

:: Pharmacogenetics, 巻 13, 番号 1, 01.01.2003, p. 29-38.

研究成果: ジャーナルへの寄稿記事

Yue, L, Saikawa, Y, Ota, K, Tanaka, M, Nishimura, R, Uehara, T, Maeba, H, Ito, T, Sasaki, T & Koizumi, S 2003, 'A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity', Pharmacogenetics, 巻. 13, 番号 1, pp. 29-38. https://doi.org/10.1097/00008571-200301000-00005
Yue, Lijie ; Saikawa, Yutaka ; Ota, Kazuhisa ; Tanaka, Motohiro ; Nishimura, Ryosei ; Uehara, Takahiro ; Maeba, Hideaki ; Ito, Takashi ; Sasaki, Takuma ; Koizumi, Shoichi. / A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. :: Pharmacogenetics. 2003 ; 巻 13, 番号 1. pp. 29-38.
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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",
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AU - Saikawa, Yutaka

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AU - Tanaka, Motohiro

AU - Nishimura, Ryosei

AU - Uehara, Takahiro

AU - Maeba, Hideaki

AU - Ito, Takashi

AU - Sasaki, Takuma

AU - Koizumi, Shoichi

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