Antiestrogens breast cancer treatment

The main potential utility of the pure antiestrogens is in the treatment of breast cancer. Several studies on their effects on the breast demonstrate both the pure antiestrogenic action of the tested compounds and their beneficial effects on breast cancer treatment. In experiments conducted in nude mice xenotrans-planted with two different human estradiol-dependent breast tumors, a single injection of fulvestrant provided an antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks (Wakeling et al. 1991). Additionally, RU 58668 was able to induce up to 30% disappearance of MCF-7 breast... 

Van de Velde P, Nique F, Bremaud J, Hameau MC, Philibert D, Teutsch G (1995) Exploration of the therapeutic potential of the antiestrogen RU 58668 in breast cancer treatment. Ann NY Acad Sci 761 164-175... 

Tumors that are steroid hormone-sensitive may be either (1) hormone-responsive, where the tumor regresses following treatment with a specific hormone (2) hormone-dependent, where removal of a hormonal stimulus causes tumor regression or (3) both. Hormone treatment of responsive tumors is usually only palliative, except in the case of the cytotoxic effect of glucocorticoids (for example, prednisone) on lymphomas. Removal of hormonal stimuli from hormone-dependent tumors can be accomplished by surgery, for example, in the case of orchiectomy for patients with advanced prostate cancer, or by drugs, for example in the case of breast cancer, treatment with the antiestrogen... 

Jordan VC, et al. (1993) Update breast cancer treatment and prevention with antiestrogens in the 1990s. Endocrine Reviews 1 82. 

For the purposes of this article, antiestrogens are compounds that counteract the biological activity of estrogens at the receptor level. In the late 1970s, there were no steroidal antiestrogens in widespread clinical use. Clomiphene [911 -45-5]( ) and tamoxifen/7(954(9-25 -/7(9) were nonsteroidal antiestrogens that had been employed for the treatment of female infertility and breast cancer, respectively. 

A stmcturally related series of phenyfiiydrazones resulted ia the selection of compound A-007 [2675-35-6] (DEKK-TEC)(37) for the treatment of hormone-dependent tumors. A-007 is an antiestrogen that, ia contrast to tamoxifen, demonstrated inhibitory activity both ia the presence and absence of estradiol ia ZR-75-1 estrogen-dependent human breast cancer cells, and afforded more protection than tamoxifen ia the 7,12-dimethylbenz[i7]anthracene... 

Hormonal therapies that have been studied in the treatment of primary or early breast cancer include antiestrogens, oophorectomy, ovarian irradiation, luteinizing hormone-releasing hormone (LHRH) agonists, and aromatase inhibitors. 

EM-800 (SCH-57050) and its active metabolite EM-652 (acolbifene, SCH-57068), are highly potent antiestrogens in human breast and uterine cancer cells in vitro as well as in vivo in nude mice and are currently undergoing clinical trials in the treatment of hormone-dependent breast cancer and endometrial cancer (Labrie et al 1999). Acolbifene shows a higher capacity of binding to... 

Pure antiestrogens, which act by different mechanisms of action, probably are not affected by the mechanisms of tamoxifen resistance. As a result, those compounds might be a good choice as second-line hormonotherapy of breast cancer after failure of tamoxifen treatment, as has been reported in clinical... 

It seems reasonable that pure antiestrogens might be used as a good alternative to tamoxifen in the treatment of breast cancer, due to their beneficial effects, without increasing the risk of endometrium cancer (Simard et al. 1997). 

Twenty-four cyclopropyl compounds were screened for their antiproliferative activities, eighteen were found to be active and five appeared to be promising pure antiestrogens, superior to tamoxifen 128 not only in the treatment of the estrogen-dependent tamoxifen-responsive breast cancer patients, but also in the treatment of the estrogen-independent, tamoxifen non-responsive, breast cancer patients. 

Eulvestrant has been evaluated in two randomised phase III trials in postmenopausal women with advanced disease after progression on prior antiestrogen therapy. In both trials, fulvestrant was at least as effective as anas-trozole. In a prospectively designed combined analysis of the results from both trials, median time to progression (TTP) was 5.5 months for fulvestrant versus 4.1 months for anastrozole [172]. Eulvestrant and tamoxifen have been compared as first-line treatments in a trial including post-menopausal women with advanced breast cancer. In this study, the between-treatment difference was non-significant (median TTP 6.8 versus 8.3 months) [173]. 

Another therapeutic role for estrogens is in the treatment of cancer. In androgen-dependent prostate carcinoma, estrogens are used therapeutically to suppress androgen formation and thus tumor growth. Estrogens are also used to treat inoperable breast cancer in men and postmenopausal women. However, antiestrogens, such as tamoxifen, have fewer side effects and are usually preferred (see section 5.8.4). 

Premature ovarian failure can be induced in offspring exposed in utero by active metabolites such as 6-mercaptopurine. Tamoxifen (treatments for breast cancer) and clomiphene (to induce ovulation) are antiestrogens that can inhibit uterine decidual induction in pseudopregnant rats. 

Tamoxifen, the antiestrogen most widely used for the treatment of breast cancer, has shown clear clinical benefits in advanced breast cancer, its efficacy being comparable with that achieved by ablative and additive therapies (Furr and Jordan, 1984) (Fig. 1). In the first clinical studies, initiated in 1969, tamoxifen was found to achieve remissions in advanced breast carcinoma similar to those observed following estrogen therapy but with fewer side effects (Cole et al., 1971). Since then, because of its favorable profile and clinical efficacy, comparable with that of other endocrine therapies, including oophorectomy and estrogens, tamoxifen has become the treatment of choice for patients with advanced or metastatic breast cancer (Buchanan et al., 1986 Howell et al, 1990 Ingle etal, 1981). 

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