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

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.

Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway

“…CDA 79 A4C encoded for a lysine to glutamine amino-acid change (K27Q) and the SNP published by Yue et al, CDA 208G4A, encodes for an alanine to threonine amino-acid change (A70T). 27 The two SNPs identified in the DCK gene, DCK IVS1-1110T4C and DCK 2190A4T, did not encode for an amino-acid substitution. A synonymous (T4C) SNP at nucleotide 315 was reported in the DCTD gene.…”

Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy?

“…So far, two nonsynonymous SNPs, 79A4C (Lys27Gln) and 208G4A (Ala70Thr), have been identified in the coding region of the human CDA gene (Yue et al, 2003;Fukunaga et al, 2004;Gilbert et al, 2006;Sugiyama et al, 2007). Ethnic or racial differences in the allele frequencies of these SNPs have been reported, as shown in Table 1.…”

“…Ethnic or racial differences in the allele frequencies of these SNPs have been reported, as shown in Table 1. Remarkable reduction in activity of 70Thr CDA was reported in vitro (Yue et al, 2003) and in vivo (Sugiyama et al, 2007), while only marginal reduction in activity of 27Gln CDA was observed in vitro (Yue et al, 2003;Gilbert et al, 2006). On the other hand, Fitzgerald et al (2006) investigated SNPs in the promoter region of CDA in vitro and in vivo, and found that some promoter CDA haplotypes might affect CDA activity.…”

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704

“…However, sensitivity to cytarabine was not changed by introducing homozygous variant CDA Gln 27 Gln polymorphism in this in vitro model. 21 We were unable to assess CDA enzymatic activity using blood samples and correlate it with CDA genotype in this study.…”