title: Pharmacogenetics of adjuvant breast cancer treatment with cyclophosphamide, epirubicin and 5-fluorouracil.
abstract: OBJECTIVE
  Most adjuvant breast cancer treatment regimens include the combination of an anthracycline (epirubicin or doxorubicin) and the alkylating agent cyclophosphamide. This study sought to investigate the influence of pharmacogenetics on the pharmacokinetics and metabolism of these agents.
  
  
  METHODS
  Blood samples were taken from patients treated with cyclophosphamide (n = 51) and epirubicin (n = 35), with or without 5-fluorouracil (5-FU). The pharmacokinetics and metabolism of the three drugs were investigated, together with pharmacogenetic investigations for cyclophosphamide and epirubicin. Cyclophosphamide and its metabolites and also epirubicin and epirubicinol were measured in plasma. DNA was extracted from whole blood and genotyping performed using RT-PCR.
  
  
  RESULTS
  Patients with at least one variant CYP2C19*17 allele had a longer CP half-life (p = 0.007), as did homozygous variants for the CYP2B6*6 allele. There was no significant effect of GSTP1, CYP2B6*2, CYP2B6*5 or CYP2C19*2 on any pharmacokinetic parameter of CP. An NQO2 exonic SNP was associated with a higher exposure to epirubicinol relative to epirubicin (p = 0.011). Other polymorphic variants of NQO1, carbonyl reductase, UGT enzymes and transporters had no influence on epirubicin or its metabolite.
  
  
  CONCLUSIONS
  Overall, pharmacogenetic factors had only a minor influence on cyclophosphamide or anthracycline-based adjuvant therapy of breast cancer.
authors: Northern Institute for Cancer Research Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors: David
authors: D
authors: Jamieson
authors: Jo
authors: J
authors: Lee
authors: Nicola
authors: N
authors: Cresti
authors: Rosanna
authors: R
authors: Jackson
authors: Melanie
authors: M
authors: Griffin
authors: Julieanne
authors: J
authors: Sludden
authors: Mark
authors: M
authors: Verrill
authors: Alan V
authors: AV
authors: Boddy
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics; D001711:Biotransformation / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003520:Cyclophosphamide / Q000378:metabolism / Q000493:pharmacokinetics; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D015251:Epirubicin / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000378:metabolism / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008875:Middle Aged
chemical_list: D000970:Antineoplastic Agents; D015251:Epirubicin; D003520:Cyclophosphamide; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D005472:Fluorouracil