title: Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity.
abstract: 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.
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Leskelä
authors.forename: C
authors.initials: C
authors.lastname: Jara
authors.forename: L J
authors.initials: LJ
authors.lastname: Leandro-García
authors.forename: A
authors.initials: A
authors.lastname: Martínez
authors.forename: J
authors.initials: J
authors.lastname: García-Donas
authors.forename: S
authors.initials: S
authors.lastname: Hernando
authors.forename: A
authors.initials: A
authors.lastname: Hurtado
authors.forename: J C C
authors.initials: JC
authors.lastname: Vicario
authors.forename: C
authors.initials: C
authors.lastname: Montero-Conde
authors.forename: I
authors.initials: I
authors.lastname: Landa
authors.forename: E
authors.initials: E
authors.lastname: López-Jiménez
authors.forename: A
authors.initials: A
authors.lastname: Cascón
authors.forename: R L
authors.initials: RL
authors.lastname: Milne
authors.forename: M
authors.initials: M
authors.lastname: Robledo
authors.forename: C
authors.initials: C
authors.lastname: Rodríguez-Antona
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000368:Aged; D000483:Alleles; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D020258:Neurotoxicity Syndromes / Q000175:diagnosis / Q000209:etiology*; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013030:Spain
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel