title: Simulation with cells in vitro of tamoxifen treatment in premenopausal breast cancer patients with different CYP2D6 genotypes.
abstract: OBJECTIVE
  Tamoxifen is a prodrug that is metabolically activated by 4-hydroxylation to the potent primary metabolite 4-hydroxytamoxifen (4OHT) or via another primary metabolite N-desmethyltamoxifen (NDMTAM) to a biologically active secondary metabolite endoxifen through a cytochrome P450 2D6 variant system (CYP2D6). To elucidate the mechanism of action of tamoxifen and the importance of endoxifen for its effect, we determined the anti-oestrogenic efficacy of tamoxifen and its metabolites, including endoxifen, at concentrations corresponding to serum levels measured in breast cancer patients with various CYP2D6 genotypes (simulating tamoxifen treatment).
  
  
  METHODS
  The biological effects of tamoxifen and its metabolites on cell growth and oestrogen-responsive gene modulation were evaluated in a panel of oestrogen receptor-positive breast cancer cell lines. Actual clinical levels of tamoxifen metabolites in breast cancer patients were used in vitro along with actual levels of oestrogens observed in premenopausal patients taking tamoxifen.
  
  
  RESULTS
  Tamoxifen and its primary metabolites (4OHT and NDMTAM) only partially inhibited the stimulant effects of oestrogen on cells. The addition of endoxifen at concentrations corresponding to different CYP2D6 genotypes was found to enhance the anti-oestrogenic effect of tamoxifen and its metabolites with an efficacy that correlated with the concentration of endoxifen; at concentrations corresponding to the extensive metabolizer genotype it further inhibited the actions of oestrogen. In contrast, lower concentrations of endoxifen (intermediate and poor metabolizers) had little or no anti-oestrogenic effects.
  
  
  CONCLUSIONS
  Endoxifen may be a clinically relevant metabolite in premenopausal patients as it provides additional anti-oestrogenic actions during tamoxifen treatment.
authors: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors: Philipp Y
authors: PY
authors: Maximov
authors: Russell E
authors: RE
authors: McDaniel
authors: Daphne J
authors: DJ
authors: Fernandes
authors: Valeriy R
authors: VR
authors: Korostyshevskiy
authors: Puspanjali
authors: P
authors: Bhatta
authors: Thomas E
authors: TE
authors: Mürdter
authors: David A
authors: DA
authors: Flockhart
authors: V Craig
authors: VC
authors: Jordan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D061986:MCF-7 Cells; D017697:Premenopause; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C016601:afimoxifene; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6; C028787:N-desmethyltamoxifen