Pharmacological characterization of 4-hydroxy-n-desmethyl-tamoxifen (ENDOXIFEN) AND 4-hydroxy-tamoxifen (4OHTAM)

Abstract

Tamoxifen is an important drug for the treatment and prevention of breast cancer. This drug is extensively oxidized to several metabolites, some of which have notably increased potency relative to the parent drug. We characterized the pharmacological properties of endoxifen with respect to the binding affinity, anti-proliferative activity, and effects on the expression of estrogen-regulated genes, in comparison with those of 4OHTAM. In estrogen receptor (ER) binding assays, endoxifen and 4OHTAM showed identical binding affinity for the α- and β-estrogen receptors. Both compounds antagonized 17β-estradiol (E2)-stimulated growth of several ER-positive breast cancer cell lines equipotently (IC50 ~50nM). In expression studies of estrogen-regulated genes using northern blot and real-time RT-PCR, endoxifen and 4OHTAM showed similar inhibitory potency towards estrogen-induced pS2 and progesterone receptor mRNA expression. These data strongly suggest that endoxifen has essentially equivalent activity to 4OHTAM. Since human plasma concentrations of endoxifen are ~7-fold higher than 4OHTAM following therapeutic doses of tamoxifen in breast cancer patients, we suggest that endoxifen is the major active metabolite of tamoxifen in vivo. Clinical Pharmacology & Therapeutics (2004) 75, P19–P19; doi: 10.1016/j.clpt.2003.11.073