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PubMed2006

[Fulvestrant].

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Adult↗
PubMed2004

interferon regulatory factor-1 mediates the proapoptotic but not cell cycle arrest effects of the steroidal antiestrogen ICI 182,780 (faslodex, fulvestrant).

Antiestrogens induce both cytostasis (cell cycle arrest) and apoptosis, but the relationship between these end points and the signaling that regulates their induction are unclear. We have previously implicated the transcription factor and putative tumor suppressor IFN regulatory factor-1 (IRF-1) in acquired antiestrogen resistance (Gu et al., Cancer Res, 62: 3428-3437, 2002). We now show the functional significance of IRF-1 in affecting antiestrogen responsiveness in estrogen receptor-positive antiestrogen-sensitive models (MCF-7, T47D, and ZR-75-1), a model of acquired antiestrogen resistance (MCF7/LCC9; estrogen receptor positive), and a model of de novo antiestrogen resistance (MDA-MB-231; estrogen receptor negative). Basal IRF-1 mRNA expression is lower in MCF7/LCC9 cells when compared with MCF-7, T47D, and ZR-75-1 cells. IRF-1 transcriptional activity in MCF-7/LCC9 cells is 18-fold lower than that seen in the parental cells (MCF-7/LCC1) and is comparable with that in MDA-MB-231 cells. Although IRF-1 mRNA expression is induced by ICI 182,780 in sensitive cells, this regulation is lost in MCF-7/LCC9 and is absent in MDA-MB-231 cells. Loss of IRF-1 regulation appears specific to antiestrogen resistance-resistant cells induce IRF-1 mRNA in response to the cytotoxic drug doxorubicin. A dominant-negative IRF-1 eliminates the ICI 182,780-induced apoptotic response (reduced >4-fold) and reduces MCF-7 and T47D cell sensitivity to the antiproliferative effects of ICI 182,780. This effect is not mediated by changes in cell cycle distribution; rather, dominant-negative IRF-1 reduces ICI 182,780-induced apoptosis. These data identify a novel mechanism of antiestrogen resistance and implicate IRF-1 as a key component in signaling some ER-mediated effects on apoptosis/cell survival.

Apoptosis↗
PubMed2005

The nuclear factor kappa B inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells.

The molecular mechanisms underlying the acquisition of resistance to the antiestrogen Faslodex are poorly understood, although enhanced expression and activity of nuclear factor kappaB (NFkappaB) have been implicated as a critical element of this phenotype. The purpose of this study was to elucidate the mechanism by which NFkappaB up-regulation contributes to Faslodex resistance and to determine whether pharmacologic inhibition of NFkappaB by the small molecule parthenolide could restore Faslodex-mediated suppression of cell growth. Basal expression of multiple NFkappaB-related molecules in MCF7-derived LCC1 (antiestrogen-sensitive) and LCC9 (antiestrogen-resistant) breast cancer cells was determined, and cells were treated with Faslodex or parthenolide. The effect of these drugs either singly or in combination was assessed by cell proliferation, estrogen receptor (ER)-dependent transcriptional activation, cell cycle analysis, and apoptosis assays. Expression of the p65 NFkappaB subunit and the upstream NFkappaB regulator IkappaB kinase gamma/NFkappaB essential modulator were increased in the resistant MCF7/LCC9 cells (P=0.001 and 0.04, respectively). Whereas MCF7/LCC9 cells were unresponsive to Faslodex alone, parthenolide effectively inhibited MCF7/LCC9 cell proliferation and the combination of Faslodex and parthenolide resulted in a 4-fold synergistic reduction in cell growth (P=0.03). This corresponded to a restoration of Faslodex-induced apoptosis (P=0.001), with no observable changes in ER-dependent transcription or cell cycle phase distribution. Because parthenolide has shown safety in Phase I clinical trials, these findings have direct clinical relevance and provide support for the design of clinical studies combining antiestrogens and parthenolide in ER-positive breast cancer.

Antineoplastic Agents↗
PubMed2005

[Fulvestrant].

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Antineoplastic Agents, Hormonal↗
PubMed2007

Oestrogen receptor antagonist and hair regrowth in dogs with hair cycle arrest (alopecia X).

An oestrogen receptor pathway that regulates the telogen-anagen hair follicle transition in mice has been described. The purpose of this study was to investigate whether fulvestrant, a pure oestrogen receptor antagonist, would cause hair regrowth in Pomeranian dogs with hair cycle arrest (alopecia X). Eleven Pomeranian dogs with hair cycle arrest were randomly assigned to receive two intramuscular injections of either 10 mg kg(-1) fulvestrant (n = 6) or an equal volume of saline (n = 5) 1 month apart. Complete blood count, chemistry panel, and urinalysis were monitored prior to the first injection and monthly for 2 months. Dogs were evaluated each month for degree of hair growth, percentage of body affected, and quality of new hair growth. Three control dogs received fulvestrant after the completion of the study. In addition, one control dog and one treatment dog received two subcutaneous injections of 20 mg kg(-1) fulvestrant 1 month apart. No dogs that received 10 mg kg(-1) fulvestrant had any evidence of hair regrowth. The control dog that received 20 mg kg(-1) fulvestrant had substantial hair regrowth 1 month after the first injection. No adverse effects from the treatment were noted. Fulvestrant does not appear to be a feasible treatment for dogs with hair cycle arrest (alopecia X) when administered intramuscularly at 10 mg kg(-1). A higher dose of fulvestrant requires more investigation but may be cost-prohibitive.

Alopecia↗
PubMed2002

Estrogen receptor downregulators: new antihormonal therapy for advanced breast cancer.

BACKGROUND: Fulvestrant is the first agent in the new class of estrogen receptor (ER) downregulators to be evaluated in clinical studies. The binding of ER downregulators to ERs inhibits the activation functions of the receptors (AF-1 and AF-2). ER downregulators also disrupt the dimerization and nuclear localization of ERs. In contrast to ER downregulators, when selective estrogen receptor modulators (SERMs) bind to ERs, only AF-2 is inhibited; AF-1 remains active. Therefore, with SERMs, AF-1 can still recruit coactivators, which results in a partially inactivated transcription and a reduced rate of tumor cell division. Consistent with its mechanism of action, animal models have shown that fulvestrant demonstrates a longer suppression of tumor growth than does tamoxifen, and it has antitumor activity in tamoxifen-resistant tumors. Two Phase III trials have been conducted comparing fulvestrant (250 mg IM monthly) with anastrozole (1 mg oral tablet daily) in postmenopausal patients with advanced breast cancer progressing after prior endocrine therapy. Objective response in fulvestrant-treated patients in the 2 studies ranged from 17.5% to 20.7% compared with 15.7% to 17.5% for anastrozole-treated patients, and the median duration of response ranged from 14.3 to 19.3 months in the fulvestrant group compared with 10.5 to 14.0 months in the anastrozole group. No statistically significant differences were demonstrated for any of the predefined end points. In both studies, fulvestrant was as well tolerated as anastrozole. OBJECTIVE: This review describes the pharmacology, clinical activity, safety, dosing, and pharmacokinetic profile of fulvestrant. CONCLUSIONS: Based on evidence to date, fulvestrant will likely be an important agent in the treatment of tamoxifen-resistant metastatic breast cancer.

Animals↗
PubMed2002

A new estrogen receptor antagonist--an overview of available data.

Fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist with no known agonist effects that downregulates the ER, is the first in a new class of antiestrogen. Consequently, fulvestrant is not cross-resistant with other endocrine therapies. In previously untreated postmenopausal women, fulvestrant brought about dose-dependent reductions in ER and progesterone receptor (PgR) protein concentrations and produced no demonstrable estrogen agonist effect. Fulvestrant has demonstrated clinical benefit rates of 69% in postmenopausal women with advanced tamoxifen-resistant breast cancer. In two global phase III trials, fulvestrant was shown to be at least as effective as the aromatase inhibitor anastrozole with similar efficacy for time to progression, objective response and clinical benefit in patients progressing on prior endocrine therapy. Fulvestrant was also well tolerated and, similar to anastrozole, maintained a good quality of life. As a once-monthly intramuscular injection, administered during clinic visits, fulvestrant offers patient compliance advantages, making this new hormonal agent a viable therapeutic option for the palliative treatment of postmenopausal women with endocrine-responsive advanced breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed2004

The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer.

Tamoxifen is one of the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting proliferation of breast epithelial cells. However, tamoxifen has estrogenic agonist effects in other tissues such as bone and endometrium due to liganded ER activating target genes in these different types of cell. Several novel anti-estrogen compounds have been developed which have a reduced agonist profile on breast and gynaecological tissues. These compounds offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen. In advanced breast cancer clinical data exist for two groups of agents: the selective estrogen receptor modulators (SERMs), further divided into "tamoxifen-like" (e.g. toremifene, droloxifene and idoxifene) and "fixed ring" compounds (e.g. raloxifene, arzoxifene and EM-800), and the selective estrogen receptor down-regulators (SERDs; e.g. fulvestrant (ICI 182780), SR 16234 and ZK 191703) also termed "pure anti-estrogens". In phase II trials in tamoxifen-resistant metastatic breast cancer the SERMs show low objective response rates (range 0-15%), suggesting cross resistance with tamoxifen. Randomized phase III trials for toremifene and idoxifene in over 1500 patients showed no significant difference compared with tamoxifen. Fewer clinical data exist for the "fixed ring" SERMs and it remains unclear whether any clinical advantage exists for the "fixed ring" SERMs over tamoxifen as first-line therapy. The main advantage for SERMs such as tamoxifen and raloxifene probably remains in early-stage disease (adjuvant therapy or prevention). Fulvestrant and the other SERDs have a high affinity for the estrogen receptor (ER) compared to tamoxifen, but none of its agonist activities. Of the SERDs, only fulvestrant has entered the clinic and this new agent is showing promising clinical activity in the treatment of advanced breast cancer. Recently published phase III studies have shown fulvestrant to be at least as effective as the third-generation aromatase inhibitor anastrozole in patients whose disease has relapsed or progressed on prior endocrine therapy. Surprisingly, however, in a phase III trial versus tamoxifen for the first-line therapy of advanced breast cancer fulvestrant did not attain the requirements for equivalence to tamoxifen, and in terms of time-to-treatment failure was inferior (5.9 versus 7.8 months for fulvestrant and tamoxifen, respectively; P=0.029). Future clinical studies will evaluate fulvestrant in the neoadjuvant setting together with its optimal sequencing in relation to tamoxifen and other endocrine therapies in advanced disease.

Antineoplastic Agents, Hormonal↗
PubMed2006

Pure oestrogen antagonists for the treatment of advanced breast cancer.

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 offulvestrant. 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.

Antineoplastic Agents↗
PubMed2005

Life following aromatase inhibitors--where now for endocrine sequencing?

The third-generation non-steroidal aromatase inhibitors (AIs) are challenging tamoxifen as treatments of choice for early and advanced breast cancer in postmenopausal women with estrogen receptor (ER)-positive disease. However, patients who initially respond to AIs eventually develop resistance to treatment and experience disease progression. To establish the optimal endocrine therapy following AI resistance, it is essential to understand the mechanisms that contribute to the loss of response. Data from in vitro models have suggested that acquired AI resistance is due to enhanced sensitization to low estrogen levels during long-term estrogen deprivation (LTED). Cross-talk between the ER and various growth-factor-receptor signaling pathways, including human epidermal growth factor receptor 2, and the insulin-like growth factor pathway, may also be implicated. Therefore, endocrine therapies that abolish estrogen signaling via removal of the ER could be effective in patients with AI-resistant disease. Fulvestrant ('Faslodex') is a new ER antagonist with no agonist effects that binds, blocks and degrades the ER. Due to its unique mode of action and lack of cross-resistance with existing treatments, fulvestrant is an effective therapeutic agent for use in sequential endocrine regimens. Fulvestrant has established efficacy in tamoxifen-resistant disease and there is a growing body of evidence demonstrating its efficacy in patients with AI-resistant disease. In preclinical models, MCF-7 cells undergoing LTED are refractory to tamoxifen but sensitive to fulvestrant, suggesting fulvestrant is a more appropriate choice following AI resistance. The steroidal AI, exemestane is also an option in non-steroidal AI-resistant disease. Clinical trials are underway to compare fulvestrant with exemestane as an appropriate therapy following the onset of AI resistance.

Anastrozole↗