Responses to Pure Antiestrogens (ICI 164384, ICI182780) in Estrogen‐Sensitive and‐Resistant Experimental and Clinical Breast Cancera

Nicholson, Robert Ian; Gee, Julia Margaret Wendy; Manning, David L.; Wakeling, A. E.; Montano, Monica M.; Katzenellenbogen, Benita S.

doi:10.1111/j.1749-6632.1995.tb31376.x

Cited by 81 publications

(47 citation statements)

References 33 publications

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“…In vitro, fulvestrant significantly decreased ER protein levels and inhibited PgR expression in MCF-7 cells (McClelland et al 1996). In contrast, tamoxifen increased MCF-7 ER (oestrogen withdrawal has a similar effect) and PgR protein levels (Horowitz & McGuire 1978, Nicholson et al 1995, Early Breast Cancer Trialists' Collaborative Group 1998, Hutcheson et al 2003. In vivo, a single 5 mg dose of fulvestrant (short-acting formulation) was as effective as tamoxifen (10 mg/kg/day orally) in blocking the growth of MCF-7 xenografts in nude mice (Wakeling et al 1991).…”

Section: Biological Effects Of Pure Oestrogen Antagonistsmentioning

confidence: 99%

Pure oestrogen antagonists for the treatment of advanced breast cancer

Howell¹

2006

Endocr Relat Cancer

108

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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: Biological Effects Of Pure Oestrogen Antagonistsmentioning

confidence: 99%

Pure oestrogen antagonists for the treatment of advanced breast cancer

Howell¹

2006

Endocr Relat Cancer

108

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“…Fulvestrant does not produce conformational changes in the ER that elicit DNA or coactivator binding or AF-1 and AF-2 activation and lacks estrogen agonist activity in a wide range of tissue, cell, and promoter contexts (McDonnell et al, 2002;Osborne et al, 2004). Fulvestrant also decreases ER␣ levels in breast cancer cells by alterations in ER trafficking that hasten proteolytic degradation (Nicholson et al, 1995;Wittmann et al, 2007) and is thus considered a selective estrogen receptor downregulator. The small ligand-binding cavity of ERR␥ is ill-suited for the bulky steroid nucleus and side chain of fulvestrant (Greschik et al, 2002(Greschik et al, , 2004, and high-throughput ligand discovery efforts have not identified fulvestrant as an ERR␥ ligand (Coward et al, 2001;Tremblay et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen Regulation of Bone Growth and Endocrine Function in the Ovariectomized Rat: Discrimination of Responses Involving Estrogen Receptor α/Estrogen Receptor β, G Protein-Coupled Estrogen Receptor, or Estrogen-Related Receptor γ Using Fulvestrant (ICI 182780)

Fitts¹,

Klein²,

Powers³

2011

J Pharmacol Exp Ther

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Tamoxifen is a selective estrogen receptor (ER) modulator, but it is also a deactivating ligand for estrogen-related receptor-␥ (ERR␥) and a full agonist for the G protein-coupled estrogen receptor (GPER). Fulvestrant is a selective ER down-regulator that lacks agonist effects on ER␣/ER␤, is inactive on ERR␥, but acts as a full agonist on GPER. Fulvestrant effects on tamoxifen actions on uterine and somatic growth, bone, the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis, and pituitary prolactin were analyzed to pharmacologically discriminate tamoxifen effects that may be mediated by ER␣/ER␤ versus ERR␥ versus GPER. Ovariectomized rats received tamoxifen (0.6 mg/kg/daily) plus fulvestrant at 0, 3, 6, or 12 mg/kg/daily for 5 weeks; controls received vehicle or 6 mg/kg fulvestrant daily. Tamoxifen effects to increase uterine weight, decrease serum IGF-I, increase pituitary prolactin, and increase bone mineral density could be fully blocked by fulvestrant, indicating mediation by ER␣/ER␤. Tamoxifen effects to decrease pituitary GH, tibia length, and body weight were only partially blocked by fulvestrant, indicating involvement of mechanisms unrelated to ER␣/ER␤. Fulvestrant did not inhibit tamoxifen actions to reduce total pituitary protein, again indicating effects not mediated by ER␣/ER␤. Tamoxifen actions to reduce serum GH were mimicked rather than inhibited by fulvestrant, pharmacological features consistent with GPER involvement. However, fulvestrant alone increased IGF-I and also blocked tamoxifen-evoked IGF-I decreases; thus fulvestrant effects on serum GH might reflect increased IGF-I feedback inhibition. Fulvestrant alone had no effect on the other parameters. The findings indicate that mechanisms unrelated to ER␣/ER␤ contribute to tamoxifen effects on body weight, bone growth, and pituitary function. IntroductionTamoxifen is an estrogen receptor (ER) ligand that is characterized as a selective ER modulator (SERM); it acts as estrogen agonist on some targets while acting as an antagonist or partial agonist on others. This is not attributed to differing pharmacological actions on ER␣ versus ER␤, but reflects the diversity of mechanisms mediating ER actions at different targets.In classic models of ER function, estrogen binding to the ligand-binding domain (LBD) transforms ER conformation and enhances ER binding to specific target gene DNA sequences (McDonnell et al., 2002;Smith and O'Malley, 2004). One or both of two ER transactivation domains (AF-1 and AF-2) then bind coactivator proteins that alter gene transcription via the recruitment of chromatin-remodeling complexes and other factors. AF-1 is located in the ER N terminus and is ligand-independent, whereas AF-2 in the LBD is ligand-dependent. Involvement of AF-1 or AF-2 in estrogen responses varies from target to target depending on the genes, cell types, coactivators, and other signaling systems involved.SERMs transform ER conformation in a manner that activates DNA binding and AF-1-dependent gene expression in classic models o...

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“…ICI 182,780 (ICI, fulvestrant, Faslodex) is an estrogen receptor antagonist, as binding to ERα causes a conformational change disabling both AF-1 and AF-2. Furthermore, the ICI-ERα complex is unstable, resulting in accelerated degradation of the ERα protein (20). ICI is used as an adjuvant endocrine therapy to treat ER-positive metastatic breast cancers in postmenopausal women with disease progression following the first line of antiestrogen therapy, as tamoxifen-as well as aromatase-resistant tumors might remain sensitive to ICI treatment (21).…”

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confidence: 99%

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Movérare‐Skrtic

Börjesson

Farman

et al. 2014

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

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Significance Estrogen exerts important effects in the skeleton, which are primarily mediated via estrogen receptor (ER)α, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. Previous studies demonstrate that ERα ligands might act as agonists, partial agonists, or antagonists. We demonstrate that the ERα antagonist ICI 182,780 (ICI) acts in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. Importantly, ICI exerted a pronounced inverse agonistic activity in the growth plate of mice lacking ERαAF-2. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.

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Responses to Pure Antiestrogens (ICI 164384, ICI182780) in Estrogen‐Sensitive and‐Resistant Experimental and Clinical Breast Cancera

Cited by 81 publications

References 33 publications

Pure oestrogen antagonists for the treatment of advanced breast cancer

Pure oestrogen antagonists for the treatment of advanced breast cancer

Tamoxifen Regulation of Bone Growth and Endocrine Function in the Ovariectomized Rat: Discrimination of Responses Involving Estrogen Receptor α/Estrogen Receptor β, G Protein-Coupled Estrogen Receptor, or Estrogen-Related Receptor γ Using Fulvestrant (ICI 182780)

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

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