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A Potent Specific Pure Antiestrogen with Clinical Potential

Bioscience I [A. E. W., M. D.] and Chemistry I [J. B.], ICI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom

Previous studies from this laboratory have described a series of 7-alkylamide analogues of estradiol with pure antiestrogenic activity, exemplified by ICI 164,384. A new compound, 7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17ß-diol (ICI 182,780) has now been identified which has significantly increased antiestrogenic potency and retains pure estrogen antagonist activity. The antiuterotrophic potency of ICI 182,780 in the immature rat was more than 10-fold greater than that of ICI 164,384 (50% effective doses of 0.06 and 0.9 mg/kg, respectively). This order of magnitude increase of in vivo potency was also reflected, in part, by intrinsic activity at the estrogen receptor. The relative binding affinities of ICI 182,780 and ICI 164,384 were 0.89 and 0.19, respectively, compared with that of estradiol (1.0). Similarly, the in vitro growth-inhibitory potency of ICI 182,780 exceeded that of ICI 164,384 in MCF-7 human breast cancer cells, where 50% inhibitory concentrations of 0.29 and 1.3 nM, respectively, were recorded. ICI 182,780 was a more effective inhibitor of MCF-7 growth than 4'-hydroxytamoxifen, producing an 80% reduction of cell number under conditions where 4'-hydroxytamoxifen achieved a maximum of 50% inhibition. This increased efficacy was reflected by a greater reduction of the proportion of cells engaged in DNA synthesis in ICI 182,780-treated cell cultures compared with tamoxifen-treated cells.

Sustained antiestrogenic effects, following a single parenteral dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, antitumor activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in nude mice. A single injection of ICI 182,780 provided antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks.

The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.

¹ To whom requests for reprints should be addressed.

Received 4/10/91. Accepted 5/21/91.

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				C. J. Thompson, N. N. C. Tam, J. M. Joyce, I. Leav, and S.-m. Ho Gene Expression Profiling of Testosterone and Estradiol-17{beta}-Induced Prostatic Dysplasia in Noble Rats and Response to the Antiestrogen ICI 182,780 Endocrinology, June 1, 2002; 143(6): 2093 - 2105. [Abstract] [Full Text] [PDF]

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				T. S. Sherman, K. L. Chambliss, L. L. Gibson, M. C. Pace, M. E. Mendelsohn, S. L. Pfister, and P. W. Shaul Estrogen Acutely Activates Prostacyclin Synthesis in Ovine Fetal Pulmonary Artery Endothelium Am. J. Respir. Cell Mol. Biol., May 1, 2002; 26(5): 610 - 616. [Abstract] [Full Text] [PDF]

				S. G. Hayes, N. B. Moya Del Pino, and M. P. Kaufman Estrogen attenuates the cardiovascular and ventilatory responses to central command in cats J Appl Physiol, April 1, 2002; 92(4): 1635 - 1641. [Abstract] [Full Text] [PDF]

				M. E. Beyer, G. Yu, H. Hanke, and H. M. Hoffmeister Acute Gender-Specific Hemodynamic and Inotropic Effects of 17{beta}-Estradiol on Rats Hypertension, November 1, 2001; 38(5): 1003 - 1010. [Abstract] [Full Text] [PDF]

				J. F. Robertson, R. I. Nicholson, N. J. Bundred, E. Anderson, Z. Rayter, M. Dowsett, J. N. Fox, J. M. W. Gee, A. Webster, A. E. Wakeling, et al. Comparison of the Short-Term Biological Effects of 7{alpha}-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17{beta}-diol (Faslodex) versus Tamoxifen in Postmenopausal Women with Primary Breast Cancer Cancer Res., September 1, 2001; 61(18): 6739 - 6746. [Abstract] [Full Text] [PDF]

				T. W. Chan, M. Pollak, and H. Huynh Inhibition of Insulin-like Growth Factor Signaling Pathways in Mammary Gland by Pure Antiestrogen ICI 182,780 Clin. Cancer Res., August 1, 2001; 7(8): 2545 - 2554. [Abstract] [Full Text] [PDF]

				E. Bonnelye, L. Merdad, V. Kung, and J.E. Aubin The Orphan Nuclear Estrogen Receptor-Related Receptor {alpha} (Err{alpha}) Is Expressed Throughout Osteoblast Differentiation and Regulates Bone Formation in Vitro J. Cell Biol., May 28, 2001; 153(5): 971 - 984. [Abstract] [Full Text] [PDF]

				G. A. Figtree, C. M. Webb, and P. Collins Tamoxifen Acutely Relaxes Coronary Arteries by an Endothelium-, Nitric Oxide-, and Estrogen Receptor-Dependent Mechanism J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 519 - 523. [Abstract] [Full Text]

				M. E. Nuttall, G. B. Stroup, P. W. Fisher, D. P. Nadeau, M. Gowen, and L. J. Suva Distinct mechanisms of action of selective estrogen receptor modulators in breast and osteoblastic cells Am J Physiol Cell Physiol, November 1, 2000; 279(5): C1550 - C1557. [Abstract] [Full Text] [PDF]

				C. K. Osborne and S. A. W. Fuqua Selective Estrogen Receptor Modulators: Structure, Function, and Clinical Use J. Clin. Oncol., September 17, 2000; 18(17): 3172 - 3186. [Abstract] [Full Text] [PDF]

				X. Chen, C. Danes, M. Lowe, T. W. Herliczek, and K. Keyomarsi Activation of the Estrogen-Signaling Pathway by p21WAF1/CIP1 in Estrogen Receptor-Negative Breast Cancer Cells J Natl Cancer Inst, September 6, 2000; 92(17): 1403 - 1413. [Abstract] [Full Text] [PDF]

				J. Odum and J. Ashby Neonatal Exposure of Male Rats to Nonylphenol Has No Effect on the Reproductive Tract Toxicol. Sci., August 1, 2000; 56(2): 400 - 404. [Abstract] [Full Text] [PDF]

				A. Gandhi, P. A. Holland, W. F. Knox, C. S. Potten, and N. J. Bundred Effects of a Pure Antiestrogen on Apoptosis and Proliferation within Human Breast Ductal Carcinoma in Situ Cancer Res., August 1, 2000; 60(15): 4284 - 4288. [Abstract] [Full Text]

				P. Parini, B. Angelin, A. Stavreus-Evers, B. Freyschuss, H. Eriksson, and M. Rudling Biphasic Effects of the Natural Estrogen 17{beta}-Estradiol on Hepatic Cholesterol Metabolism in Intact Female Rats Arterioscler Thromb Vasc Biol, July 1, 2000; 20(7): 1817 - 1823. [Abstract] [Full Text] [PDF]

				G. A. Figtree, H. Griffiths, Y.-Q. Lu, C. M. Webb, K. MacLeod, and P. Collins Plant-derived estrogens relax coronary arteries in vitro by a calcium antagonistic mechanism J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1977 - 1985. [Abstract] [Full Text] [PDF]

				G. D. Charles, M. J. Bartels, T. R. Zacharewski, B. B. Gollapudi, N. L. Freshour, and E. W. Carney Activity of Benzo[a]pyrene and Its Hydroxylated Metabolites in an Estrogen Receptor-{alpha} Reporter Gene Assay Toxicol. Sci., June 1, 2000; 55(2): 320 - 326. [Abstract] [Full Text] [PDF]

				K.-M. Lau, M. LaSpina, J. Long, and S.-M. Ho Expression of Estrogen Receptor (ER)-{{alpha}} and ER-{beta} in Normal and Malignant Prostatic Epithelial Cells: Regulation by Methylation and Involvement in Growth Regulation Cancer Res., June 1, 2000; 60(12): 3175 - 3182. [Abstract] [Full Text]

				S. Kennedy Endocrine Disruptors: Overview and a Pathologist's Perspective Toxicol Pathol, May 1, 2000; 28(3): 418 - 419. [PDF]

				J. Komi and O. Lassila Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells Blood, May 1, 2000; 95(9): 2875 - 2882. [Abstract] [Full Text] [PDF]

				L. C. Hodges, J. S. Bergerson, D. S. Hunter, and C. L. Walker Estrogenic Effects of Organochlorine Pesticides on Uterine Leiomyoma Cells in Vitro Toxicol. Sci., April 1, 2000; 54(2): 355 - 364. [Abstract] [Full Text] [PDF]

				A. Huang, D. Sun, A. Koller, and G. Kaley 17{beta}-Estradiol Restores Endothelial Nitric Oxide Release to Shear Stress in Arterioles of Male Hypertensive Rats Circulation, January 4, 2000; 101(1): 94 - 100. [Abstract] [Full Text] [PDF]

				K. C. Reinhart, R. K. Dubey, P. J. Keller, U. Lauper, and M. Rosselli Xeno-oestrogens and phyto-oestrogens induce the synthesis of leukaemia inhibitory factor by human and bovine oviduct cells Mol. Hum. Reprod., October 1, 1999; 5(10): 899 - 907. [Abstract] [Full Text] [PDF]

				M. Sabbah, D. Courilleau, J. Mester, and G. Redeuilh Estrogen induction of the cyclin D1 promoter: Involvement of a cAMP response-like element PNAS, September 28, 1999; 96(20): 11217 - 11222. [Abstract] [Full Text] [PDF]

				G. A. Figtree, Y.-q. Lu, C. M. Webb, and P. Collins Raloxifene Acutely Relaxes Rabbit Coronary Arteries In Vitro by an Estrogen Receptor–Dependent and Nitric Oxide–Dependent Mechanism Circulation, September 7, 1999; 100(10): 1095 - 1101. [Abstract] [Full Text] [PDF]

				J. I. MacGregor Schafer, H. Liu, D. A. Tonetti, and V. C. Jordan The Interaction of Raloxifene and the Active Metabolite of the Antiestrogen EM-800 (SC 5705) with the Human Estrogen Receptor Cancer Res., September 1, 1999; 59(17): 4308 - 4313. [Abstract] [Full Text] [PDF]

				D. Ghosh, J. A. Taylor, J. A. Green, and D. B. Lubahn Methoxychlor Stimulates Estrogen-Responsive Messenger Ribonucleic Acids in Mouse Uterus through a Non-Estrogen Receptor (Non-ER){alpha} and Non-ER{beta} Mechanism Endocrinology, August 1, 1999; 140(8): 3526 - 3533. [Abstract] [Full Text]