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Titolo:
Destabilization of steroid receptors by heat shock protein 90-binding drugs: A ligand-independent approach to hormonal therapy of breast cancer
Autore:
Bagatell, R; Khan, O; Paine-Murrieta, G; Taylor, CW; Akinaga, S; Whitesell, L;
Indirizzi:
Univ Arizona, Steele Mem Childrens Res Ctr, Dept Pediat, Tucson, AZ 85724 USA Univ Arizona Tucson AZ USA 85724 s Ctr, Dept Pediat, Tucson, AZ 85724 USA Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA Univ Arizona Tucson AZ USA 85724 , Arizona Canc Ctr, Tucson, AZ 85724 USA Kyowa Hakko Kogyo Co Ltd, Pharmaceut Res Inst, Shizuoka 100, Japan Kyowa Hakko Kogyo Co Ltd Shizuoka Japan 100 es Inst, Shizuoka 100, Japan
Titolo Testata:
CLINICAL CANCER RESEARCH
fascicolo: 7, volume: 7, anno: 2001,
pagine: 2076 - 2084
SICI:
1078-0432(200107)7:7<2076:DOSRBH>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
FIRST-LINE THERAPY; ESTROGEN-RECEPTOR; PROGESTERONE-RECEPTOR; POSTMENOPAUSAL WOMEN; MOLECULAR CHAPERONE; HSP90-BINDING AGENT; ENDOCRINE THERAPY; TERMINAL DOMAIN; MUTATED P53; CROSS-TALK;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
43
Recensione:
Indirizzi per estratti:
Indirizzo: Bagatell, R Univ Arizona, Steele Mem Childrens Res Ctr, Dept Pediat, 1501 N Campbell Ave, Tucson, AZ 85724 USA Univ Arizona 1501 N Campbell Ave Tucson AZ USA 85724 85724 USA
Citazione:
R. Bagatell et al., "Destabilization of steroid receptors by heat shock protein 90-binding drugs: A ligand-independent approach to hormonal therapy of breast cancer", CLIN CANC R, 7(7), 2001, pp. 2076-2084

Abstract

Steroid hormone receptors have become an important target in the management of breast cancers. Despite a good initial response rate, however, most tumors become refractory to current hormonal therapies within a year of starting treatment. To address this problem, we evaluated the effects of agents that bind the molecular chaperone heat shock protein 90 (Hsp90) on estrogenreceptor function in breast cancer. Unstimulated estrogen and progesteronereceptors exist as multimolecular complexes consisting of the hormone-binding protein itself and several essential molecular chaperones including Hsp90, We found that interaction of the Hsp90-binding drugs geldanamycin and radicicol with the chaperone destabilizes these hormone receptors in a ligand-independent manner, leading: to profound and prolonged depletion of theirlevels in breast cancer cells cultured in vitro. Consistent with these findings, in vivo administration of the geldanamycin derivative 17-allylaminogeldanamycin (17AAG; NSC330507) to estrogen-supplemented, tumor-bearing SCIDmice resulted in marked depletion of progesterone receptor levels in both uterus and tumor. Drug administration also delayed the growth of established, hormone-responsive MCF-7 and T47D human tumor xenografts for up to 3 weeks after the initiation of therapy. We conclude that in light of their novel mechanism of antihormone action, consideration should be given to examining the activity of 17AAG and other Hsp90-binding agents in patients with refractory breast cancer in future clinical trials, either alone or in combination with conventional hormone antagonists.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/21 alle ore 02:19:31