Anti-estrogen

Resistance to tamoxifen is a complex phenomenon and there is evidence that relapse under tamoxifen therapy is linked to the estrogenicity of the drug. Both, the great success of tamoxifen and its liabilities have boosted the search for new analogues in the past 25 years with the goal of identifying a compoimd with increased anti-tumour activity and with reduced side effects. A second generation of structurally related triphenyl-ethylenes like 

Approaches from medicinal chemistry that resulted in the discovery of first-and second-generation SERMS have been reviewed extensively [149] and will not be discussed in this section. The more recently published chemical structures of anti-estrogen were derived from different classes, e.g. stilbestriol. 

ICI 164,384 and fulvestrant (ICI 182,780) (Fig. 13) represent the first generation of pure anti-estrogens with ER destabilising activity [146]. These compounds are 7-a-substituted analogues of 17/f-estradiol. SAR studies identified fulvestrant (ICI 182,780), a compoimd with significantly increased antiestrogenic potency. As fulvestrant has a very low bioavailabiUty when administered orally it has to be applied by intramuscular injection [146]. 

TAS-108 (SR16234) is a novel and orally active steroidal compound with a proposed additional molecular mode-of-action that is different from that of SERMs such as tamoxifen and raloxifene [157]. TAS-108 is a full estrogen receptor-a antagonist, and it should also recruit co-activator transcriptional intermediary factor 2 to ER-j6, which may have a preventive effect on bone loss [157]. 

From a clinical perspective, tamoxifen is still the first and only SERM worth mentioning from the first- and second-generation compounds. The pharmacology of tamoxifen has been reviewed extensively [142]. The NSABP-11 adjuvant trial and the Breast Cancer Prevention Trial (BCPT-1) are some of the milestones in the history of tamoxifen [141]. 

---

Organ weights and tissue development in rats administered both endosulfan and estradiol were not significantly different from those seen in rats that received estradiol alone. The study results indicate that endosulfan was neither estrogenic nor anti-estrogenic under the conditions of this assay. 

Legler J, van den Brink C, Brouwer A, et al. 1998. Assessment of (anti-)estrogenic compounds using a stably transfected luciferase reporter gene assay in the human T47-D breast cancer cell line. Organohalogen Compounds 37 265. 

Tran, D.Q., Ide, C.R, and McLachlan, J.A. et al. (1996). The anti-estrogenic activity of selected polynuclear aromatic hydrocarbons in yeast expressing human estrogen receptor. Biochemical and Biophysical Research Communications 229, 102-108. 

Yamaguchi and Gao, 1998 Rat femoral-metaphyseal tissues cultured for 48 h with bone resorbing factors PTH, PGE2 or EPS) +/- genistein measured bone calcium content, acid and alkaline phosphatases Genistein (10 Yi O M) inhibited bone resorption. Effect reversed by anti-estrogen, tamoxifen. 

However, the estrogenic and anti-estrogenic activity of isoflavonoids could... 

Dopp E, voLLMER G, HAHNEL c, GREVESMUHL Y and SCHIFFMANN D (1999) Modulation of tile intracellular calcium level in mammalian cells caused by ivp-estradiol, different phytoestrogens and the anti-estrogen ICl 182780. JSteroid Biochem Mol Biol. 68 (1-2) 57-64. 

An improved version of the Knoevenagel reaction between acetophenones and aldehydes allows direct access to trarcr-2,3-disubstituted chroman-4-ones, examples of which show high anti-estrogenic activity <00T1811>. Reduction of flavanones by NaBUi leads to the 2,4-cis-flavan-4-ols from which 4-methoxyflavans can readily be obtained detailed H and 13C NMR data are provided <00T6047>. 

Barsalou A, Gao W, Anghel SI, Carriere J, Mader S (1998) Estrogen response elements can mediate agonist activity of anti-estrogens in human endometrial Ishikawa cells. J Biol Chem 273 17138-17146... 

Lim KB, Ng CY, Ong CK, Ong CS, Tran E, Nguyen TT, Chan GM, Huynh H (2001) Induction of apoptosis in mammary gland by a pure anti-estrogen ICI 182780. Breast Cancer Res Treat 68 127-138... 

In recent studies, tetramethrin exhibited anti-estrogenic activity in some assays [158], but not in others [159]. 

Huang ES, Nelson FR. 1986. Anti-estrogenic action of chlordecone in rat pituitary gonadotrophs in vitro. Toxicol Appl Pharmacol 82 62-69. 

Several potent anti-estrogens also have a potential to be used as 17/f-HSD inhibitors because some of them have a dual site of inhibitory action they block both the estrogen receptor (anti-estrogen effect) and estrogen formation (inhibitory effect on 17/f-HSD). Despite the complexity of a dually active agent, such inhibitors have interesting properties suitable for their potential use in the treatment of estrogen-sensitive diseases, but their potency and selectivity for 17/1-HSDl have to be improved [98]. 

Fig. 12 Chemical structures of first and second generation non-steroidal anti-estrogens (tamoxifen and derivatives), and novel third generation SERMs...

---