Additional Pure Antiestrogens

Jordan is supported by the Department of Defense Breast Program under award number BC050277 Center of Excellence (Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense), SPORE in Breast Cancer CA 89018, R01 GM067156, FCCC Core Grant NIH P30 CA006927, the Avon Foundation and the Weg Fund of Fox Chase Cancer Center. 

1 Berry, D.A., Cronin, K.A., Plevritis, S.K., Fryback, D.G., Clarke, L., Zelen, M., Mandelblatt, J.S., Yakovlev, A.Y., Habbema, J.D. and Feuer, E.J. (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. The New England Journal of Medicine, 353, 1784—1792. 

2 Million Women Study Collaborators. (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet, 362, 419-427. 

7 Jensen, E.V. (1962) On the mechanism of estrogen action. Perspectives in Biology and Medicine, 6, 47-59. 

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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... 

Fig. 8. Schematic representation of the ligand-induced changes in the confirmation of ER that lead to activities ranging from pure estrogenic (A) to pure antiestrogenic (D) effects. In addition to the ligand-induced changes in the three-dimensional structure of ER, the multiple interactions with cell-specific coactivators and corepressors determine the final activity of each ER-ligand complex in each cell type.

Fig. 23. Time course of the effect of treatment with the pure antiestrogen EM-800 or tamoxifen at the daily oral dose of 50 pg, 150 pg, or 400 pg for 4 months on the average size of ZR-75-1 human breast cancer xenografts in ovariectomized nude mice supplemented with an implant of estrone. The size of tumors at start of treatment was 31.1 0.8 mm2. Ovariectomized mice receiving the vehicle alone were used as additional controls. Results are expressed as percentage of pretreatment values (means + SEM of 28 to 37 tumors per group) (Couillard et al., 1998a).

The consequence of the partial agonistic activity of tamoxifen is that complete blockade of the action of estrogens cannot be achieved with tamoxifen (Wakeling, 1993) or the other compounds demonstrated to exert stimulatory effects, reversible with EM-652 on the proliferation of human breast cancer cells and alkaline phosphatase in human endometrial carcinoma cells. It is thus reasonable to expect that the availability of a pure antiestrogen, in addition to avoiding the risk of inducing endometrial carcinoma, should provide significant benefits over tamoxifen in the treatment of breast cancer. 

Tamoxifen resistance is caused, in part, by its intrinsic agonist activity at the ER. in addition, tamoxifen oniy inhibits the AF-2 activation pathway but does not piay a roie in AF-1 pathway inhibition. Pure antiestrogens do not possess any estrogenic activity in any species or target tissue and, therefore, offer an additionai avenue of treatment when resistance to tamoxifen occurs, in addition, because they are devoid of estrogenic action, these agents cannot be ciassified as SERMs. 

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