Phase II, Randomized, Double-Blind Study of Two Dose Levels of Arzoxifene in Patients With Locally Advanced or Metastatic Breast Cancer

Buzdar, Aman U.; O’Shaughnessy, Joyce; Booser, Daniel J.; Pippen, John; Jones, Stephen E.; Münster, Pamela N.; Peterson, Patrick; Melemed, Allen S.; Winer, Eric P.; Hudis, Clifford A.

doi:10.1200/jco.2003.06.108

Cited by 65 publications

(41 citation statements)

References 12 publications

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“…One of the phenolic groups ( Figure 7) is methylated to provide protection from Phase II metabolism. Nevertheless, arzoxifene has not performed well as a treatment for breast cancer [110,111]; higher doses are less effective than lower doses. These data imply that effective absorption is impaired by phase III metabolism.…”

Section: Metabolic Mimicrymentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.

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Section: Metabolic Mimicrymentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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“…Based on its partial oestrogen agonist effects (Delmas et al 1997), raloxifene is also currently being used for the prevention and treatment of osteoporosis and breast cancer. Arzoxifene showed promising initial results in a phase II study in advanced breast cancer, although its efficacy was greater in tamoxifen-sensitive than tamoxifen-resistant disease (Buzdar et al 2003).…”

Section: Introductionmentioning

confidence: 99%

“…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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“…Replacement of the 4Ј-hydroxyl group of DMA by the 4Ј-methoxy of Arz reduces firstpass glucuronidation and increases ClogP by approximately 0.6 unit (Sato et al, 1998). Arz is observed to be metabolically desmethylated to yield DMA, both in vitro and in clinical samples after Arz treatment (Buzdar et al, 2003;Liu et al, 2005a). Because DMA is markedly more potent, Arz could be seen as a DMA prodrug.…”

Section: Discussionmentioning

confidence: 96%

Structural Modulation of Oxidative Metabolism in Design of Improved Benzothiophene Selective Estrogen Receptor Modulators

Qin¹,

Kastrati²,

Ashgodom³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Raloxifene and arzoxifene are benzothiophene selective estrogen receptor modulators (SERMs) of clinical use in postmenopausal osteoporosis and treatment of breast cancer and potentially in hormone replacement therapy. The benefits of arzoxifene are attributed to improved bioavailability over raloxifene, whereas the arzoxifene metabolite, desmethylarzoxifene (DMA) is a more potent antiestrogen. As polyaromatic phenolics, benzothiophene SERMs undergo oxidative metabolism to electrophilic quinoids. The long-term clinical use of SERMs demands increased understanding of correlations between structure and toxicity, with metabolism being a key component. A homologous series of 4-substituted 4-desmethoxyarzoxifene derivatives was developed, and metabolism was studied in liver and intestinal microsomes. Formation of glutathione conjugates was assayed in rat liver microsomes and novel adducts were characterized by liquid chromatography-tandem mass spectrometry.Formation of glucuronide conjugates was assayed in human intestine and liver microsomes, demonstrating formation of glucuronides ranging from 5 to 100% for the benzothiophene SERMs: this trend was inversely correlated with the loss of parent SERM in rat liver microsomal incubations. Molecular orbital calculations generated thermodynamic parameters for oxidation that correlated with Hammett substituent constants; however, metabolism in liver microsomes correlated with a combination of both Hammett and Hansch lipophilicity parameters. The results demonstrate a rich oxidative chemistry for the benzothiophene SERMs, the amplitude of which can be powerfully modulated, in a predictable manner, by structural tuning of the 4-substituent. The predicted extensive metabolism of DMA was confirmed in vivo and compared with the relatively stable arzoxifene and F-DMA.

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Phase II, Randomized, Double-Blind Study of Two Dose Levels of Arzoxifene in Patients With Locally Advanced or Metastatic Breast Cancer

Cited by 65 publications

References 12 publications

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

Pure oestrogen antagonists for the treatment of advanced breast cancer

Structural Modulation of Oxidative Metabolism in Design of Improved Benzothiophene Selective Estrogen Receptor Modulators

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