Abstract
Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with postmenopausal women’s health, including hormone responsive cancer and osteoporosis. Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or prevent and treat breast cancer.The search for the ‘ideal’ SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic potential of these compounds can be obtained.In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.
Highlights
In this article, we describe the discovery and development of the group of medicines called SERMs
The idea of using a chemical to prevent breast cancer is a noble goal that has achieved significant successes in the past three decades. This is not a new concept as Professor Antoine Lacassagne [1] had the vision which he stated at the Annual Meeting of the American Association for Cancer Research in 1936: “If one accepts the consideration of adenocarcinoma of the breast as a consequence of a special hereditary sensibility to the proliferative action of oestrone, one is led to imagine a therapeutic preventive for subjects predisposed by their heredity to this cancer, to stop the congestion of oestrone in the breast.”
In the days before atorvastatin was proven to reduce low density lipoprotein (LDL) cholesterol [67] and as a result reduce the risk of coronary heart disease due to atherosclerosis [68,69,70], a variety of drugs that interfered with cholesterol metabolism were evaluated
Summary
As a result of the finding in the laboratory [18], Fornander and colleagues [19] reported a significant increase in the risk of developing endometrial cancer during tamoxifen therapy. Tamoxifen maintained and built bone in postmenopausal women with node negative (low risk recurrence) breast cancer [25] This result demonstrated, for the first time in a prospective randomized clinical trial, that the principle of “selective estrogenic (bone) and antiestrogenic (breast) action” occurred in humans. The initial discovery with the bone building effects of tamoxifen and raloxifene [21] coupled with the demonstration of the inhibition of rat mammary carcinogenesis with either tamoxifen and raloxifene [20] prompted the description of a vision for the future use of the new class of drugs [2, 23]. The rat mammary carcinogenesis studies with tamoxifen and raloxifene showed that the effect of raloxifene was not superior to tamoxifen and would not be long lasting [23] This would be demonstrated subsequently in postmenopausal women in the STAR trial [32]
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