Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline‐related congestive heart failure after childhood cancer

摘要: BACKGROUND. Exposure to anthracyclines as part of cancer therapy has been associated with the development congestive heart failure (CHF). The potential role genetic risk factors in anthracycline-related CHF remains be defined. Thus, this study, authors examined whether common polymorphisms candidate genes involved pharmacodynamics (in particular, nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 gene NQO1 and carbonyl reductase 3 CBR3) had an impact on CHF. METHODS. A nested case–control study was conducted within a cohort 1979 patients enrolled Childhood Cancer Survivor Study who received treatment available DNA. Thirty (cases) 115 matched controls were genotyped for (NQO1*2) CBR3 (the valine [V] methionine [M] substitution at position 244 [V244M]). Enzyme activity assays recombinant isoforms (CBR3 V244 M244) anthracycline substrate doxorubicin used investigate functional V244M polymorphism. RESULTS. Multivariate analyses adjusted sex primary disease recurrence test associations between (NQO1*2 V244M) CHF. Analyses indicated no association NQO1*2 polymorphism (odds ratio [OR], 1.04; P = .97). There trend toward (OR, 8.16; .056 G/G vs A/A; OR, 5.44; .092 G/A A/A). In line, (G allele) synthesized 2.6-fold more cardiotoxic doxorubicinol per unit time than M244 (A allele; [8.26 ± 3.57 nmol/hour.mg] [3.22 0.67 nmol/hour.mg]; .01). CONCLUSIONS. The may have among childhood survivors by modulating intracardiac formation alcohol metabolites. Larger confirmatory studies are warranted. 2008. © 2008 American Society.