Effects of high dose raloxifene in selected patients with advanced breast carcinoma

Gradishar, William J.; Glusman, J. E.; Lü, Yifei; Vogel, Charles L.; Cohen, Fredric J.; Sledge, George W.

doi:10.1002/(sici)1097-0142(20000501)88:9<2047::aid-cncr10>3.0.co;2-e

Cited by 88 publications

(26 citation statements)

References 27 publications

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“…1)) such as raloxifene, arzoxifene and ERA-923 were then developed. Most of these have demonstrated anti-tumour activity in breast cancer but also have some partial agonist activity (Buzdar et al 1988, Gradishar et al 2000, Munster et al 2001, Buzdar et al 2003. Results from the Study of Tamoxifen and Raloxifene (STAR) trial, one of the largest breast cancer prevention studies, which has recruited 19 000 postmenopausal women at risk of breast cancer, are expected in 2006.…”

Section: Introductionmentioning

confidence: 99%

Pure oestrogen antagonists for the treatment of advanced breast cancer

Howell¹

2006

Endocr Relat Cancer

107

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For more than 30 years, tamoxifen has been the drug of choice in treating patients with oestrogen receptor (ER)-positive breast tumours. However, research has endeavoured to develop agents that match and improve the clinical efficacy of tamoxifen, but lack its partial agonist effects. The first 'pure' oestrogen antagonist was developed in 1987; from this, an even more potent derivative was developed for clinical use, known as fulvestrant (ICI 182,780, 'Faslodex'). Mechanistic studies have shown that fulvestrant possesses high ER-binding affinity and has multiple effects on ER signalling: it blocks dimerisation and nuclear localisation of the ER, reduces cellular levels of ER and blocks ER-mediated gene transcription. Unlike anti-oestrogens chemically related to tamoxifen, fulvestrant also helps circumvent resistance to tamoxifen. There are extensive data to support the lack of partial agonist effects of fulvestrant and, importantly, its lack of cross-resistance with tamoxifen. In phase III studies in patients with locally advanced or metastatic breast cancer, fulvestrant was at least as effective as anastrozole in patients with tamoxifen-resistant tumours, was effective in the first-line setting and was also well tolerated. These data are supported by experience from the compassionate use of fulvestrant in more heavily pretreated patients. Further studies are now underway to determine the best strategy for sequencing oestrogen endocrine therapies and to optimise dosing regimens of fulvestrant. At present, and for the foreseeable future, fulvestrant is the only oestrogen antagonist with no agonistic effects licensed for the treatment of advanced breast cancer in postmenopausal women. Other similar oestrogen antagonists are undergoing research and development, with a few currently being evaluated in phase II trials.

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Section: Introductionmentioning

confidence: 99%

Pure oestrogen antagonists for the treatment of advanced breast cancer

Howell¹

2006

Endocr Relat Cancer

107

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“…Additionally, screens of this nature have little ability to discriminate between mechanistically distinct classes of antagonists. In the cases of the ER and AR, this is particularly problematic given the high level of cross resistance observed among different antiestrogens and antiandrogens observed in breast and prostate cancers, respectively (4,5,25). Thus conformation-based screens, such as the AR/gelsolin screen described here, capable of identifying classes of NR antagonists could speed the discovery and development of therapeutics useful in the treatment of hormone-refractory breast and prostate cancers.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists

Joseph

Wittmann

Dwyer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The impact of ligand binding on nuclear receptor (NR) structure and the ability of target cells to distinguish between different receptorligand complexes are key determinants of the pharmacological activity of NR ligands. However, until relatively recently, these mechanistic insights have not been used in a prospective manner to develop screens for NR modulators with specific therapeutic activities. Driven by the need for unique androgen receptor (AR) antagonists that retain activity in hormone-refractory prostate cancer, we developed and applied a conformation-based screen to identify AR antagonists that were mechanistically distinct from existing drugs of this class. Two molecules were identified by using this approach, D36 and D80, which interact with AR in a unique manner and allosterically inhibit AR agonist activity. Unlike the clinically important antiandrogens, casodex and hydroxyflutamide, both D36 and D80 block androgen action in cellular models of hormone-refractory prostate cancer. Mechanistically, these compounds further distinguish themselves from classical AR antagonists in that they do not promote AR nuclear translocation and quantitatively inhibit the association of AR with DNA even under conditions of overexpression. Although the therapeutic potential of these antiandrogens is apparent, it is the demonstration that it is possible, to modulate the interaction of cofactors with agonistactivated AR, using second-site modulators, that has the greatest potential with respect to the therapeutic exploitation of AR and other NRs.antiandrogen ͉ hormone-refractory

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“…Raloxifene was initially developed as a treatment for breast cancer, but early studies of women with advanced disease indicated a lack of effectiveness [17]. A recent study provides some very limited support for possible effectiveness in women with early stage, ER positive breast cancer.…”

Section: Discussionmentioning

confidence: 99%