Compositions comprising inhibitors of estrogen response

Details Compositions comprising inhibitors of estrogen response Compositions comprising inhibitors of estrogen response

1998-01-12

2000-12-05

Kemmerer, Elizabeth

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

514 45, 514211, 514280, 514455, 514456, 514651, A61K 3100, A61K 3155, A61K 3135

Patent

active

06156723&

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

Many breast tumors require estrogens for tumor growth. Thus, treatment with antiestrogen compounds can slow or prevent tumor spread. Many antiestrogens, however, show both estrogen antagonistic and agonistic activity. The nonsteroidal antiestrogen tamoxifen, for example, which is established as the treatment of choice for the endocrine therapy of advanced breast cancer, shows both agonistic and antagonistic activity. Sutherland, S. & Jackson, M. Cancer Treat. Revs. 15: 183-194 (1987).
The agonistic activity of tamoxifen and other antiestrogens may have profound effects upon patients. For example, agonistic activity may have beneficial effects, such as preventing osteoporosis and reducing serum cholesterol. Love, et al. New Eng. J Med. 326: 852-856 (1992). Love, et al. J. Natl. Cancer Inst. 82: 1327-1332 (1990). Conversely, agonistic activity may also be harmful. Tamoxifen for example sometimes increases endometrial tumor incidence lino, et al. Cancer Treat. & Res. 53: 228-237 (1991) or switches from inhibition to stimulation of estrogen dependent growth in breast tumor progression. Parker, M.G. (ed) Cancer Surveys 14: Growth Regulation by Nuclear Hormone Receptors. Cold Spring Harbor Laboratory Press (1992).
It is desirable to identify pure antiestrogens as they are anticipated to provide more rapid, complete or longer-lasting tumor responses. Wakeling, A. E. Breast Cancer Res. & Treat. 25: 1-9 (1993). For example, ICI 164,384 (hereinafter referred to as "ICI"), thought to be a pure antiestrogen, blocked MCF-7 cell invasion activity of a re-constituted basement membrane while estradiol and 4'-hydroxytamoxifen stimulated this activity suggesting that early treatment of breast cancer with a pure antiestrogen might be particularly beneficial in limiting tumor spread. Braacke, et al., Br. j Cancer63: 867-872 (1991).
Conversely, while pure antiestrogens appear preferable for cancer treatments, mixed agonist-antagonist compounds may be preferable for preventative treatment. Such compounds should combine sufficient antagonist activity on estrogen stimulated breast tumor growth while maintaining simultaneous agonist activity on bone density and serum lipid levels.
In addition, a number of non-steroidal natural and synthetic compounds found in the environment have been shown to possess estrogenic activity. For instance, plant flavonoids including genistein and coumestrol and synthetic compounds such as phenolphthalein, alkylphenols, and dihydroxystilbenes, have been shown to be agonists of the estrogen receptor (Miksicek, Mol. Pharmacol. 44:37-43 (1993); Nieto et al., Biochem. Int. 21:305-311 (1990); White et al., Endocrinology 135:175-182 (1994); Makela et al., Environ. Health Perspect. 102:572-578 (1994); Krishnan et al. Endocrinology 132:2279-2286 (1993)).
Environmental estrogens, or xenoestrogens, are suspected of playing a role in the causation of a number of diseases such as breast and other cancers. In addition, such compounds may be implicated in human infertility and problems in wildlife reproduction. In the case of breast and other cancers, established risk factors (e.g., genetic factors) do not always account for the high levels of these diseases. Evidence suggests that lifetime exposure to various xenoestrogens may be important in the induction of breast cancer. To the extent such xenoestrogens are important in diseases such as breast cancer, reduction in exposure to these compounds should be critical to reducing cancer risks (Davis et al. Environmental Health Perspectives101:372-377 (1993)).
Currently, antiestrogen compounds or xenoestrogenic compounds are screened with animal models such as the rat uterine test. These tests are cumbersome, slow, expensive and of uncertain application to humans because of differences between the human and rodent estrogen receptors.
The prior art fails to provide methods for quickly and easily testing potential antiestrogen compounds for agnostic as well as antagonistic properties mediated through pathways other than the classical estrogen r

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