Tamoxifen estrogen-like effects

The finding that tamoxifen given as adjuvant to surgery improved survival (Fisher et al., 1996) and decreased bone loss (Evans and Turner, 1995 Jordan, 1993) has been a major stimulus to search for other and possibly more potent and specific compounds that would act as antiestrogens in the breast and uterus while having estrogen-like effects in the skeletal and cardiovascular systems. 

The first-generation pure antiestrogen ICI 164,384 (Figure 5.29) is a 7a-substituted derivative of E2 that has no detectable estrogen-like properties in vivo or in vitro [375, 380]. The compound was identified in a search for drugs that do not possess the estrogen-like effects of tamoxifen and that would, as a result, be more effective antitumor agents. 

Webb, P., Lopez, G.N., Uht, R.M. and Kushner, P.J. (1995) Tamoxifen activation of the estrogen receptor/AP-1 pathway potential origin for the cell-specific estrogen-like effects of antiestrogens. Molecular Endocrinology, 9, 443-456. 

Stimulated by the need for an improved therapy for breast cancer, considerable efforts have been devoted to the synthesis of compounds that would exert pure antiestrogenic activity in the mammary gland and uterus. As mentioned above, while tamoxifen has beneficial effects on breast cancer, it clearly acts as an estrogen agonist in the endometrium, leading to an increased rate of endometrial carcinoma in women taking tamoxifen under chronic conditions. Moreover, it is most likely that a pure antiestrogen will have beneficial effects superior to those of tamoxifen in breast cancer prevention and treatment. 

The evidence that tamoxifen was able to exert estrogenic effects on several tissues like the bone (Love et al. 1992) opened the door to the concept of SERMs, which is explained in detail in Chaps. 2 and 3 of this book. The mechanisms of action of these substances on ERs is explained in detail in Chap. 3. However, it is pertinent to comment on some special aspects of its action on mammary cancer cells. IGF-1 is a key element in growth control of malignant breast cells through endocrine and paracrine pathways. Tamoxifen and its active metabolite are able to inhibit IGF-l-stimulated growth (Jordan... 

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... 

Anastrozole, a selective nonsteroidal inhibitor of aromatase (the enzyme required for estrogen synthesis. Figures 40-2 and 40-5), is effective in some women whose breast tumors have become resistant to tamoxifen (see Chapter 54). Letrozole is similar. Exemestane, a steroid molecule, is an irreversible inhibitor of aromatase. Like anastrozole and letrozole, it is approved for use in women with advanced breast cancer (see Chapter 54). 

Because of the absence of protective effects of raloxifene on vasomotor symptoms or hot flashes, many authors suggest that conventional estrogen replacement therapy is likely to remain the intervention of choice for the prevention of bone loss in symptomatic postmenopausal women (Baynes and Compston, 1998). In fact, since the majority of women seek medical attention because of vasomotor symptoms (Gam-brell, 1996) and the compounds of the SERM class, such as raloxifene (Draper et al., 1996), can lead to exacerbation (Draper et al., 1996) or have no influence (Delmas et al., 1997) on these symptoms, compliance is likely to be a problem. In fact, even tamoxifen has been shown to increase hot flashes (Love etal, 1991a). 

Raloxifene Like tamoxifen, which is also a SERM (see p 266), raloxifene s [ra LOCKS ih feen] actions are mediated through the estrogen receptors, and it has both estrogenic and antiestrogenic effects. Its clinical use is based on its ability to decrease bone resorption and overall bone turnover. However, unlike estrogen and tamoxifen, it apparently has little to no effect on the endometrium, and therefore may not predispose to uterine cancer. Raloxifene lowers total cholesterol and LDL in the serum, but has no effect on HDL or triglycerides. [Note Whether the latter... 

Among the adverse effects, climacteric-like complaints predominate, reflecting the decline in estrogen levels. Unlike the SERMs, tamoxifen, which is used for the same indication, aromatase inhibitors do not promote endometrial growth and do not increase the risk of thromboembolic complications. 

Raloxifene Raloxifene is used for prevention of osteoporosis in postmenopausal women. It has partial agonist effects on bone and increases serum HDL. Like tamoxifen, raloxifene has antagonist effects in breast tissue and reduces the incidence of breast cancer in women who are at very high risk. Unlike tamoxifen, the drug has no estrogenic effects on endometrial tissue. Adverse effects include hot flushes and increased risk of venous thrombosis. 

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