Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo

Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo

Author Dardes, Rita de Cássia de Maio Autor UNIFESP Google Scholar
O'Regan, R. M. Google Scholar
Gajdos, C. Google Scholar
Robinson, S. P. Google Scholar
Bentrem, D. Google Scholar
De los Reyes, A. Google Scholar
Jordan, V. C. Google Scholar
Institution Northwestern Univ
Universidade Federal de São Paulo (UNIFESP)
Dupont Pharmaceut Co
Abstract Purpose: Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth.Experimental Design: Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-naive tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen IC1182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor a expression by different ligands.Results: Estradiol and GW5638 down-regulated the receptor compared with control. IC1182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-naive breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-naive endometrial tumor after 14 weeks. GW5638 and IC1182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice.Conclusions: GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-naive endometrial cancer. More importantly, GW5638, like the pure antiestrogen IC1182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.
Language English
Date 2002-06-01
Published in Clinical Cancer Research. Birmingham: Amer Assoc Cancer Research, v. 8, n. 6, p. 1995-2001, 2002.
ISSN 1078-0432 (Sherpa/Romeo, impact factor)
Publisher Amer Assoc Cancer Research
Extent 1995-2001
Origin http://clincancerres.aacrjournals.org/content/8/6/1995
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000176141900042
URI http://repositorio.unifesp.br/11600/43350

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