Selective Estrogen Receptor Modulators And Antiestrogens

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Whereas estrogens have been very important in chemical contraception and HRT, compounds that can antagonize the ER have been of great interest for the treatment of estrogen-dependent breast cancers. Tumor biopsies have shown ER to be present in about 60% of primary breast cancers, and most are responsive to estrogen blockade. Unfortunately, most of these ER-related breast cancers also develop resistance to antiestrogen therapy within 5 years. In contrast, only about 6% of nonmalignant breast tissues have significant ER present. Three compounds that are used clinically for estrogen antagonist action in the treatment of breast cancer are tamoxifen, toremifene, and fulvestrant (Fig. 25.15). Two additional agents that can antagonize ERs are clomiphene, which is used as an ovulation stimulant, and raloxifene, which is used for the prevention and treatment of osteoporosis.

Tamoxifen and clomiphene were traditionally called ER antagonists or antiestrogens. Referring to these compounds as ER antagonists, however, does not accurately portray how these compounds work in vivo. Although tamoxifen is an ER antagonist in breast tissue, it has agonist actions on en-dometrium, liver, bone, and cardiovascular system. Because of the differential agonist and antagonist effects of these types of compounds on the ER, depending on the specific tissue, a new term was coined: selective estrogen receptor modulators (SERMs). A SERM is a drug that has tissue-specific estrogenic activity. Although many compounds exhibit SERM activity, a few agents are antagonists in all tissues. These compounds are termed antiestrogens, and fulvestrant is one example (Fig. 25.15). Tamoxifen and clomiphene are often referred to in older literature as antiestrogens.

Tamoxifen has seen extensive use in treating primary breast cancers that are ER dependent.52,53 For premenopausal women with metastatic disease, tamoxifen is an alternative and adjuvant with oophorectomy, ovarian irradiation, and mastectomy. Tamoxifen use, however, is not problem free. Tamoxifen increases the incidence of endometrial polyps, hy-perplasia and carcinoma, and uterine sarcomas. The risk of endometrial cancer resulting from tamoxifen is, however, much lower than the "modest but highly significant reductions in morbidity and mortality of breast cancer."54 Because

Tamoxifen (Novaldex)

4-Hydroxytamoxifen OH

Tamoxifen (Novaldex)

Toremifene (Fareston)

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