NEW DRUGSSelective oestrogen receptor modulators/new antioestrogens: a clinical perspective
Introduction
Oestrogen has a number of important physiological effects on hormone-dependent reproductive tissues. It controls the growth of breast epithelial tissue, regulates the menstrual cycle by promoting endometrial proliferation in the uterus, and regulates circulating cholesterol levels, thereby providing a protective effect on the cardiovascular system.1 Oestrogen also protects against the loss of bone mineral density (BMD) and cognitive function in elderly women.[1], [2], [3] The biological role of oestrogen is mediated through high-affinity binding to the oestrogen receptor (ER).4 Breast tumours that express the ER are stimulated by oestrogen5 and antioestrogen therapy has thus become an established treatment for ER-positive breast cancer.
Treatment decisions for breast cancer can be complicated due to the varied clinical course of the disease and the many different treatments available. Patients with ER-positive tumours in whom hormonal therapy may be indicated include patients with metastatic breast cancer that is not immediately life threatening. In patients with early disease, hormonal therapy may also be used as adjuvant treatment.6
Section snippets
Evolution of antioestrogen therapy
At the end of the 19th century, Beatson7 first reported that the growth of human breast carcinomas may be associated with ovarian function (i.e. hormones) and antihormonal therapy has been evolving ever since. Pharmacological doses of oestrogens began to be used as treatment for breast cancer in pre- and postmenopausal women in the early 1940s and, second to ovarian ablation, oestrogen therapy is probably the oldest form of hormonal treatment for breast cancer.8 A schematic depicting the
First-generation SERMs (triphenylethylenes)
A number of triphenylethylene derivatives have been developed. For each of these antioestrogens, pre-clinical data suggested improved efficacy and safety profiles when compared with tamoxifen.[13], [14], [15]
Toremifene
Toremifene is structurally related to tamoxifen and, due to the high probability of cross-resistance between these two antioestrogens, was developed as an alternative to tamoxifen in the hope that it would produce fewer uterotrophic effects.[16], [17], [18]
High-dose oestrogens
Triphenylchlorethylene, triphenylmethylethylene, and stilboestrol were the first synthetic oestrogens to be used to treat carcinoma of the breast, with favourable results.8 It is only relatively recently, however, that high-dose estrogens have been included in the category of SERMs, as it is now apparent that these agents have antioestrogenic effects on breast tumours. It may seem rather paradoxical that both the reduction of oestrogen levels and the administration of high-dose oestrogen can
Fulvestrant: an oestrogen receptor antagonist
Fulvestrant is the first of a new type of ER antagonist with no known agonist effects, which binds, blocks and degrades the ER. The lack of oestrogen agonist activity was first demonstrated preclinically54 and confirmed in a study in healthy volunteers.55 The latter study evaluated the effects of fulvestrant 125 and 250 mg with or without ethinyloestradiol on the endometrium in 30 healthy, postmenopausal volunteers. In addition to blocking the oestrogenic effects of oestradiol, fulvestrant had
Optimising treatment: where are we now?
Clinical data for the SERMs have been somewhat disappointing in the advanced disease setting, as the efficacy advantages over tamoxifen seen in preclinical studies have not materialised in patients. However, greater potential may exist in the adjuvant or chemoprevention setting, where beneficial effects on bone, lipid and the endometrium will be of maximum benefit. At present, third-generation AIs such as anastrozole and letrozole are the only hormonal therapies that have been demonstrated in
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Cited by (55)
Effect of estrogen on prostaglandin synthetase in bovine oviduct smooth muscle
2018, European Journal of PharmacologyCitation Excerpt :Tamoxifen is an estrogen antagonist in breast tissue. In addition, fulvestrant is estrogen receptor antagonists with no known agonist effects, which binds, blocks and degrades the estrogen receptor (Robertson, 2004). In the present study, we investigated the mechanism of action of E2 using fulvestrant and tamoxifen, selective estrogen nuclear receptor inhibitor.
Female antiestrogens
2018, Encyclopedia of ReproductionSymmetric 4,4′-(piperidin-4-ylidenemethylene)bisphenol derivatives as novel tunable estrogen receptor (ER) modulators
2016, Bioorganic and Medicinal ChemistryCitation Excerpt :Indeed, 4-hydroxytamoxifen, an active metabolite of tamoxifen, easily isomerizes from the active Z form to the inactive E form in solution and in vitro studies (Fig. 1).9 In this regard, novel SERMs having other skeletons, such as benzothiophene,10 dihydronaphthalene,11 benzopyrane,12 and steroid,13 have been developed and used as antagonistic SERMs. On the other hand, cyclofenil shows weak estrogenic activity because of the absence of the alkylamino chain, and thus it has been developed as an agonistic SERM (Fig. 1).14
Endogenous oestrogens do not regulate endothelial nitric oxide production in early postnatal rats
2015, European Journal of PharmacologyCitation Excerpt :Newborn female rats injected with ICI 182,780 had delayed uterus growth, which indicates the efficiency of chosen treatment protocol, since oestrogens stimulate uterus growth through PI3K/Akt-pathway and activation of IGF-1 and VEGF transcription (Kummer et al., 2008; Maruyama and Yoshimura, 2008). It is important to note that ICI 182,780, in contrast to other antioestrogens, displays pure antagonistic effect on ERα/β (Pinilla et al., 2002; Robertson, 2004). The effects of chronic ERα/β blockade on anticontractile action of NO were studied on saphenous artery of 10–12 days old male rats.
Identification of coregulators influenced by estrogen receptor subtype specific binding of the ER antagonists 4-hydroxytamoxifen and fulvestrant
2014, Chemico-Biological InteractionsCitation Excerpt :In contrast, fulvestrant is a full ERα and ERβ antagonist and is used as a second line breast cancer drug [29]. Fulvestrant acts by blocking both ERs and reducing cellular levels of ERα [8,30–33]. In tests for its antagonist activity towards E2, it has a 9 times higher antagonistic preference for ERα over ERβ [34].
Endocrine therapy for advanced/metastatic breast cancer
2013, Hematology/Oncology Clinics of North AmericaCitation Excerpt :Tamoxifen was compared with many other endocrine therapies in randomized trials in the early years, and although these were small and lacked statistical power by modern standards it was nevertheless consistently at least as effective or better, and often with a better toxicity profile. These findings include comparisons with high-dose estrogens,13,14 megestrol acetate (MA), the most widely used synthetic progestin,15–18 and oophorectomy in premenopausal women.19,20 Tamoxifen has been shown to be as good as other SERMs, including toremifene and idoxifene, or in some cases better (eg, droloxifene, arzoxifene); all of these were phase II crossover studies showing cross-resistance between tamoxifen and other SERMs.21–25