| 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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