PURPOSE: Tamoxifen is an effective drug for the treatment and prevention of breast cancer. It is extensively metabolized by the human cytochrome P450 enzyme system into several metabolites. Of these, 4-hydroxy-tamoxifen (4-OH-Tam) is an active metabolite, which has greater anti-estrogenic potency than the parent drug, tamoxifen. We reported recently that 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) could also be active. The progesterone receptor (PR) messenger ribonucleic acid (mRNA) expression is commonly studied as a marker of estrogenic effect in breast cancer cells and PR levels in breast cancer patients are correlated with tamoxifen response. We, therefore, determined the effect of endoxifen and 4-OH-Tam on 17beta-estradiol (E2)-induced PR mRNA expression in an estrogen receptor-positive human breast cancer cell line. METHODS: MCF-7 cells were treated with drugs for 24 h. The total ribonucleic acid (RNA) was harvested and transcribed into complementary deoxyribonucleic acids (cDNAs). The PR mRNA level was measured by using real-time reverse transcription polymerase chain reaction (RT-PCR). The PR expression data were normalized using a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression. We measured the metabolite concentrations in the cultured media by high performance liquid chromatography (HPLC) to determine whether there was conversion of one metabolite to the other. RESULTS: Consistent with previous reports, the dose-response of the E2 effect on the PR expression indicated an ED(50) value of approximately 60 pM and the maximum induction of PR mRNA was nearly ten-fold. When 10(-10) M E2 was used, induction of the PR expression was observed in 2 h and reached its maximum at 24 h. In this assay, neither endoxifen nor 4-OH-Tam alone produced any change in the PR mRNA expression. However, both endoxifen and 4-OH-Tam decreased the E2-induced PR expression with similar potency. There was very little interconversion between the two metabolites during the culture. CONCLUSIONS: Since endoxifen is present at greater concentrations than 4-OH-Tam in human plasma of breast cancer patients receiving chronic tamoxifen, these results provide further evidence that endoxifen is as important as, or more important than, 4-OH-Tam to the anti-estrogenic action of tamoxifen.
PURPOSE:Tamoxifen is an effective drug for the treatment and prevention of breast cancer. It is extensively metabolized by the human cytochrome P450 enzyme system into several metabolites. Of these, 4-hydroxy-tamoxifen (4-OH-Tam) is an active metabolite, which has greater anti-estrogenic potency than the parent drug, tamoxifen. We reported recently that 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) could also be active. The progesterone receptor (PR) messenger ribonucleic acid (mRNA) expression is commonly studied as a marker of estrogenic effect in breast cancer cells and PR levels in breast cancerpatients are correlated with tamoxifen response. We, therefore, determined the effect of endoxifen and 4-OH-Tam on 17beta-estradiol (E2)-induced PR mRNA expression in an estrogen receptor-positive humanbreast cancer cell line. METHODS: MCF-7 cells were treated with drugs for 24 h. The total ribonucleic acid (RNA) was harvested and transcribed into complementary deoxyribonucleic acids (cDNAs). The PR mRNA level was measured by using real-time reverse transcription polymerase chain reaction (RT-PCR). The PR expression data were normalized using a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression. We measured the metabolite concentrations in the cultured media by high performance liquid chromatography (HPLC) to determine whether there was conversion of one metabolite to the other. RESULTS: Consistent with previous reports, the dose-response of the E2 effect on the PR expression indicated an ED(50) value of approximately 60 pM and the maximum induction of PR mRNA was nearly ten-fold. When 10(-10) M E2 was used, induction of the PR expression was observed in 2 h and reached its maximum at 24 h. In this assay, neither endoxifen nor 4-OH-Tam alone produced any change in the PR mRNA expression. However, both endoxifen and 4-OH-Tam decreased the E2-induced PR expression with similar potency. There was very little interconversion between the two metabolites during the culture. CONCLUSIONS: Since endoxifen is present at greater concentrations than 4-OH-Tam in human plasma of breast cancerpatients receiving chronic tamoxifen, these results provide further evidence that endoxifen is as important as, or more important than, 4-OH-Tam to the anti-estrogenic action of tamoxifen.
Authors: Leticia B A Rangel; Jodi L Taraba; Christopher R Frei; Lon Smith; Gladys Rodriguez; John G Kuhn Journal: Breast Cancer Res Treat Date: 2014-11-14 Impact factor: 4.872
Authors: Thomas P Ahern; Mariann Christensen; Deirdre P Cronin-Fenton; Kathryn L Lunetta; Håvard Søiland; Jennifer Gjerde; Jens Peter Garne; Carol L Rosenberg; Rebecca A Silliman; Henrik Toft Sørensen; Timothy L Lash; Stephen Hamilton-Dutoit Journal: Cancer Epidemiol Biomarkers Prev Date: 2011-07-12 Impact factor: 4.254
Authors: Oukseub Lee; Katherine Page; David Ivancic; Irene Helenowski; Vamsi Parini; Megan E Sullivan; Julie A Margenthaler; Robert T Chatterton; Borko Jovanovic; Barbara K Dunn; Brandy M Heckman-Stoddard; Kathleen Foster; Miguel Muzzio; Julia Shklovskaya; Silvia Skripkauskas; Piotr Kulesza; David Green; Nora M Hansen; Kevin P Bethke; Jacqueline S Jeruss; Raymond Bergan; Seema A Khan Journal: Clin Cancer Res Date: 2014-07-15 Impact factor: 12.531
Authors: N I Ntukidem; A T Nguyen; V Stearns; M Rehman; A Schott; T Skaar; Y Jin; P Blanche; L Li; S Lemler; J Hayden; R M Krauss; Z Desta; D A Flockhart; D F Hayes Journal: Clin Pharmacol Ther Date: 2007-08-22 Impact factor: 6.875
Authors: Carolyn D DuSell; Erik R Nelson; Bryan M Wittmann; Jackie A Fretz; Dmitri Kazmin; Russell S Thomas; J Wesley Pike; Donald P McDonnell Journal: Mol Endocrinol Date: 2009-11-09