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  • Title: Interactions of antiestrogens with human breast cancer in long-term tissue culture.
    Author: Lippman M, Bolan G, Huff K.
    Journal: Cancer Treat Rep; 1976 Oct; 60(10):1421-9. PubMed ID: 1035504.
    Abstract:
    A variety of antiestrogens can be shown to antagonize estrogen action in animal model systems. Several of these compounds are useful in the management of metastatic human breast cancer. To further elucidate their mechanism of action, we studied several of these compounds using human breast cancer cell lines maintained in long-term tissue culture as a model system. Antiestrogens including tamoxifen (NSC-180973; ICI-46474), nafoxidine. CI-628, and clomiphene citrate inhibit macromolecular synthesis below control levels in two human breast cell lines. This effect is limited to cell lines which contain estrogen receptors. Simultaneous addition of as little as 1000-fold less estradiol prevents antiestrogen effects. Sequential addition of estrogen for up to 48 hours to cells incubated in antiestrogen reverses inhibition. If cells are continued in antiestrogen alone for more than about 3 days, inhibitory effects become irreversible. The cells detach from the surface of the culture vessel and are no longer viable. Tamoxifen competes with 3H-estradiol for specific receptor sites but with about a 100-fold lower apparent affinity. Direct binding of 3H-tamoxifen and 3H-estradiol to duplicate cytoplasmic extracts reveals equivalent numbers of binding sites but a 20-fold lower affinity for the antiestrogen. There is reasonable agreement between concentrations of tamoxifen which bind to receptor and concentrations which inhibit cells. Several antiestrogen compounds were studied using human breast cancer cell lines maintained in long-term tissue culture. Tamoxifen, nafoxidine, CI-628 (nitromifene citrate), and clomiphene citrate were shown to inhibit macromolecular synthesis below control levels, but only in 2 human breast cancer lines containing estrogen receptors. This antiestrogen effect was prevented by the simultaneous addition of 1000-fold less estradiol-17. Sequential addition of estrogen for up to 48 hours to cells incubated in antiestrogen reversed the inhibition but after 3 days of incubation with only antiestrogen, the effect was not reversible. Tamoxifen competed with tritiated-estradiol for receptor sites but with much less affinity. Direct binding of tritiated-tamoxifen and tritiated-estradiol revealed equal numbers of binding sites. The antiestrogen had a 20-fold less affinity for the binding sites. All other antiestrogens studied similarly inhibited cells to below control levels. It is concluded that antiestrogens do not act by simply competing with estrogen for receptor sites. Nuclear binding of the antiestrogen complexes has been shown to be different from estrogen-receptor complexes.
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