Title: ICI 182,780, a new antioestrogen with clinical potential.
Title Abreviation: J Steroid Biochem Mol Biol Date of Pub: 1992 Sep
Author: Wakeling AE; Bowler J;
Issue/Part/Supplement: 1-3 Volume Issue: 43 Pagination: 173-7
MESH Headings: Animal; Antineoplastic Agents (*PD); Breast Neoplasms (*DT); Cell Division (DE); Drug Screening Assays, Antitumor; Estradiol (*AA/PD); Estrogen Antagonists (*PD); Human; Receptors, Estrogen (DE); -RN-;
Journal Title Code: AX4 Publication Type: JOURNAL ARTICLE
Date of Entry: 921022N Entry Month: 9212
Country: ENGLAND Index Priority: 2
Language: Eng Unique Identifier: 92399295
Unique Identifier: 92399295 ISSN: 0960-0760
Abstract: Previous studies in this laboratory identified a series of 7 alpha-alkylamide analogues of 17 beta-oestradiol which are pure antioestrogens. Among this initial lead series of compounds, exemplified by ICI 164,384, None was of sufficient in vivo potency to merit serious consideration as a candidate for clinical evaluation. Further structure-activity studies identified a new compound, ICI 182,780, 7 alpha-[9-(4,4,5,5,5-pentafluoro-pentylsulphinyl)nonyl]oestra-1,3,5(10)- triene-3,17 beta-diol, with significantly increased antioestrogenic potency. The antiuterotrophic potency of ICI 182,780 is more than 10-fold greater than that of ICI 164,384. ICI 182,780 has no oestrogen-like trophic activity and, like ICI 164,384 is peripherally selective in its antioestrogenic effects. The increased in vivo potency of ICI 182,780 was also reflected, in part, by intrinsic activity at the oestrogen receptor and in the growth inhibitory potency of ICI 182,780 in MCF-7 human breast cancer cells. 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. Sustained antioestrogenic effects of ICI 182,780, following a single parenteral dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, the antitumour activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in athymic mice where, over a 1 month period, a single injection of ICI 182,780 in oil suspension achieved effects comparable with those of daily tamoxifen treatment. Thus, ICI 182,780 provides the opportunity to evaluate clinically the potential therapeutic benefits of complete blockade of oestrogen effects in endocrine-responsive human breast cancer.
Abstract By: Author
Address: Bioscience I and Chemistry I, Mereside Laboratories, Macclesfield, Cheshire, England.
Number of References: 15

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