RESUMO
AIMS: Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism. METHODS: We sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin-containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics. RESULTS: Two previously reported AKR1C3 intronic variants, IVS4-212 C>G and IVS4+218 G>A, were detected. The AKR1C3 IVS4-212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 10(9) vs. 3.85 ± 3.42 × 10(9) l(-1) , P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 10(9) vs. 1.56 ± 2.80 × 10(9) l(-1) , P = 0.008) and significant improvement of progression-free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2-55.8) vs. 31.0 (95% confidence interval 20.7-41.2) months, P = 0.017] and overall survival [OS; mean OS 64.4 (95% confidence interval 58.3-70.5) vs. 46.3 (95% confidence interval 35.1-57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4-212 C>G and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration-time curve and OS, ABCB1 G2677T/A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 T>G correlated with OS. The AKR1C3 IVS4-212 CAssuntos
3-Hidroxiesteroide Desidrogenases/genética
, Antibióticos Antineoplásicos/farmacocinética
, Neoplasias da Mama/genética
, Neoplasias da Mama/metabolismo
, Doxorrubicina/farmacocinética
, Hidroxiprostaglandina Desidrogenases/genética
, Polimorfismo de Nucleotídeo Único
, Subfamília B de Transportador de Cassetes de Ligação de ATP
, Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética
, Adulto
, Idoso
, Oxirredutases do Álcool/genética
, Membro C3 da Família 1 de alfa-Ceto Redutase
, Povo Asiático/genética
, Neoplasias da Mama/tratamento farmacológico
, Intervalo Livre de Doença
, Éxons/genética
, Feminino
, Genótipo
, Técnicas de Genotipagem
, Humanos
, Pessoa de Meia-Idade
, Análise Multivariada
, Proteínas de Transporte de Cátions Orgânicos/genética
, Farmacogenética