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Pharmacogenomics J ; 11(2): 121-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20212519

RESUMO

Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele)=0.55; 95% confidence interval (CI)=0.34-0.89; P=0.014 and HR (per allele)=0.51; 95%CI=0.30-0.86; and P=0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele)=1.72; 95%CI=1.05-2.82; and P=0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR=1.64 (95% CI=1.26-2.14; P=0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP3A/genética , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Paclitaxel/efeitos adversos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Idoso , Alelos , Antineoplásicos Fitogênicos/uso terapêutico , Citocromo P-450 CYP2C8 , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Neurotóxicas/diagnóstico , Paclitaxel/uso terapêutico , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único/genética , Espanha
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