Novel agents to modulate oestrogen action

Abstract

As women enter the menopause, the majority suffers symptoms associated with a dramatic fall in circulating levels of 17 beta-oestradiol and oestrone. As a result, the oestrogen protective effect against coronary artery disease and osteoporosis is lost. To solve these problems, hormone replacement therapy is often used. However, there are a number of side-effects including increased risk from breast and uterine cancer that can limit compliance. New drugs, called selective oestrogen modulators (SERMs), have been developed to mimic oestrogen's effects on the liver, heart and bones but without its harmful effects on the breast and uterus. SERMs are structurally diverse compounds that bind to oestrogen receptors and elicit agonist or antagonist responses depending on the target tissue and hormonal milieu. The drugs are being used, or evaluated, for the prevention of hormone-responsive breast cancer, osteoporosis and cardiovascular disease in postmenopausal women. Tamoxifen is the endocrine treatment of choice for breast cancer, but it also has beneficial effects on bone density and serum lipids in postmenopausal women. Recently, tamoxifen was shown to decrease the risk of invasive breast cancer in women at high risk. However, tamoxifen has some stimulatory effects on the endometrium. Raloxifene is used to prevent osteoporosis and fractures. Raloxifene also lowers circulating cholesterol and the incidence of invasive breast cancer in postmenopausal women but does not stimulate the endometrium. The SERMs have evolved from mere laboratory curiosities into drugs that hold promise for preventing several major diseases associated with ageing in women.

Expression of estrogen receptor ® in human colorectal cancer

“…The DNA binding domain (DBD) contains a two-zinc finger structure which plays an important role in receptor dimerization and in binding of receptors to specific DNA sequence. The DBDs of ERα and ERβ are highly homologous [4] . Up to now, several ERβ isoforms have been identified such as ERβ1, ERβ2, ERβ3, ERβ4, ERβ5, etc [5] .…”

Anticancer Drugs That Modulate Hormone Action

“…The outer, charged surface, which is essential for the interaction of the receptor with coactivators, is left outside (Figure 3.10a). 18 The alignment of H12 over the cavity is prevented by the binding of antagonists, exemplified by raloxifene, because their side chain is too long to fit the binding cavity and protrudes from the pocket between H3 and H11, preventing the folding of the helix H12 and hence the transcriptional activation function of the estrogen receptor ( Figure 3.10b). This helix displacement seems to be a common feature of steroidal and nonsteroidal antiestrogens with a bulky side chain.…”

What is past is prologue: estrogen/progestin replacement tomorrow

“…In contrast, raloxifene acted as an agonist at ER a and ER b in an RRE-transactivation system 40 . The SERM selectivity reflects the diversity of ER forms and the corresponding co-regulators, the differences of cell types in their expression and the diversity of ER target genes [41][42][43] .…”