Inhibitors, aromatase

Aromatase inhibitors constitute an additional antiestrogenic principle that is based upon inhibition of estrogen formation. They are used chiefly in the therapy of advanced breast cancer when the tumor has become insensitive to estrogen and the patient has completed menopause. However, one agent in this class (anastrozole) was recently licensed for use in early breast cancer. [Pg.256]

Among the adverse effects, climacteric-like complaints predominate, reflecting the decline in estrogen levels. Unlike the SERMs, tamoxifen, which is used for the same indication, aromatase inhibitors do not promote endometrial growth and do not increase the risk of thromboembolic complications. [Pg.256]

Aromatase inhibitors serve to eliminate ex-traovarian synthesis of estrogens in breast cancer patients. This can be achieved effectively only in postmenopause because, as an FSH-dependent enzyme, ovarian aromatase is subject to feedback regulation of female Luellmann, Color Atlas of Pharmacology 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. [Pg.256]

All rights reserved. Usage subject to terms and conditions of license. [Pg.257]

One approach to interfere with ER signalling is to reduce the circulating level of its ligand estradiol by inhibiting the enzyme aromatase. Aromatisation is the last step in the synthesis of estradiol. This reaction is catalysed by the P450 aromatase mono-oxygenase complex that is present in the smooth endoplasmic [Pg.34]

Development of aromatase inhibitors (AIs) began as early as the 1970s and has expanded greatly in the past three decades. Consequently, numerous comprehensive reviews on aromatase inhibitors have been published, see for example [73]. [Pg.35]

Competitive AIs are chemical compounds that compete with the substrate androstenedione for non-covalent binding to the active site of the enzyme to decrease the amount of product formed. Initially, research and development of AIs started with the synthesis and biochemical characterisation of competitive inhibitors. [Pg.35]

Steroidal AIs have been synthesised using the structure of androstenedione as starting point for the chemical optimisation programme (Fig. 6). These inhibitors bind to the aromatase in the same manner as the substrate androstenedione. The structure-activity relationship (SAR) of the androstenedione derivatives has extensively been investigated. Although several of these [Pg.36]

Recently, dual aromatase-sulfatase inhibiton (DASI) was introduced as a new targeting approach [80]. It is based on the hypothesis that additional inhibition of the steroid sulfatase (STS) should reduce estrone levels signifl- [Pg.37]

R)-3-Eth5i-3(4-pyridyl)piperidine-2,6-dione (197), useful in the treatment of certain breast cancers, is a 20-fold more potent aromatase inhibitor... [Pg.262]

Aromatase inhibitors (aminogluthetimide, formes-tane, trilostane) block the formation of estrogens from precursor steroids and thus lower estrogen levels. They have been used for treating breast cancer. [Pg.155]

In premenopausal women the ovary is the richest source of aromatase and hence estrogen. Aromatase is confined to the granulosa cells and is produced under the influence of gonadotropins (FSH and LH). Despite being a rich source of aromatase, three separate studies have shown that aromatase inhibitors are unable to sufficiently suppress ovarian estrogen production to postmenopausal levels. One explanation for this phenomenon may be a compensatory rise in gonadotrophins which maintains adequate estrogen production, despite the presence of the inhibitor. As such aromatase inhibitors cannot be used in premenopausal breast cancer patients. After menopause, ovarian... [Pg.219]

Aminooglutethimide was the fust aromatase inhibitor to be used in patients with metastatic breast cancer, where response rates of up to 30% have been reported. Unfortunately, due to its lack of selectivity for aromatase, it induced a medical adrenelectomy that resulted in suppression of aldosterone and cortisol. With the development of more selective aromatase... [Pg.219]

Anastrazole is a nonsteroidal, type H, aromatase inhibitor that is 200 times more potent than aminoglutethimide. It is eliminated primarily via hqDatic metabolism, has a terminal half life of 50 h with steady state concentrations achieved approximately 10 days with once daily dosing regimens. It is administered orally at a dose of 1 mg/day that achieves near maximal aromatase inhibition and hence estrogen suppression in breast cancer patients. No effect on adrenal steroidogenesis has been observed at up to ten times the daily recommended dose. When used in the metastatic setting, anastrozole has been shown... [Pg.220]

Like anastrozole, letrozole is a third generation, type II nonsteroidal aromatase inhibitor. Renal excretion of its... [Pg.220]

Aromatase inhibitors are relatively well tolerated however have a number of distinct side effects are observed that stem from the state of estrogen deprivation induced by aromatase inhibitors. Side effects include hot flashes, joint and muscle aches, vasomotor symptoms and vaginal dryness. Variable effects of aromatase inhibitors on lipid levels have been observed. Trials comparing third generation aromatase inhibitors to tamoxifen have also repotted an increased risk of cardiovascular events in the group receiving aromatase inhibitors. [Pg.221]

Aromatase inhibitors have also been used in premenopausal women for the treatment of endometriosis and to induce ovarian folliculogenesis as part of the treatment for infertility. [Pg.221]

Dixon MJ (2006) Aromatase inhibitors in early beast cancer therapy a variety of treatment strategies. Expert Opin 7 (18)2465-2479... [Pg.221]

Buzdar AU (2005—2006) Aromatase inhibitors changing the face of endocrine therapy for breast cancer. Breast dis 24 107-117... [Pg.221]

Pandya N, Morris GJ (2006) Toxicity of Aromatase Inhibitors. Semin Oncol 33 688-695... [Pg.221]

Aromatase inhibitors that inhibit the androgen aromatization in estrogens and thus block estrogen synthesis. [Pg.1192]

Tributyltin is well established as an aromatase inhibitor, and dibutyltin appears to have some potency also (exact characterization of the endocrine disrupting capacity of dibutyltin alone is difficult because of the presence of tributyltin as an impurity). Monobutyltin and mono- and dioctyltins have no aromatase inhibiting capacity in in vitro tests. No data are available for this end-point for the methyltins. [Pg.5]

Tributyltin is well established as an aromatase inhibitor (IPCS, 1990). Quantitative comparisons of potency cannot be defined for other organotins, because a full range of in vitro tests has not been performed. [Pg.27]

Oberdorster, E. and McClellan-Green, P. (2002). Mechanisms of imposex induction in the mud snail, Ilyanassa obsoleta TBT as a neurotoxin and aromatase inhibitor. Marine Environmental Research 54, 715-718. [Pg.363]

Cavalli A, Greco G, Novellino E, Recanatini M. Linking CoMFA and protein homology models of enzyme-inhibitor interactions an application to nonsteroidal aromatase inhibitors. Bioorg Med Chem 2000 8 2771-80. [Pg.466]

Chronic renal disease Aromatase inhibitors (anastrazole, exemestane, letrozole)... [Pg.854]

Anastrozole is a selective nonsteroidal aromatase inhibitor that lowers estrogen levels. The pharmacokinetics of anastrozole demonstrate good absorption, with hepatic metabolism the primary route of elimination and only 10% excreted unchanged by the kidney. The elimination half-life is approximately 50 hours. Anastrozole is used for the adjuvant treatment of postmenopausal women with hormone-positive breast cancer and in breast cancer patients who have had disease progression following tamoxifen. Side effects include hot flashes, arthralgias, osteoporosis/bone fractures, and thrombophlebitis. [Pg.1296]

Hormonal therapies that have been studied in the treatment of primary or early breast cancer include antiestrogens, oophorectomy, ovarian irradiation, luteinizing hormone-releasing hormone (LHRH) agonists, and aromatase inhibitors. [Pg.1314]

In postmenopausal women, recently reported evidence supporting the use of aromatase inhibitors in the adjuvant setting is intriguing and may usurp the role of tamoxifen. Three different approaches to therapy have been undertaken with these new agents (1) direct comparison with tamoxifen for adjuvant hormonal therapy, (2) sequential use after 5 years of adjuvant tamoxifen therapy, and (3) sequential use after 2 to 3 years of adjuvant tamoxifen. Based on results of several studies, it has been concluded that therapy for postmenopausal women with ER-positive breast cancer should include an aromatase inhibitor.27,47 It is still unclear if the aromatase inhibitor should be used instead of tamoxifen or sequentially after receiving tamoxifen for 2 to 5 years.27 Concerns surrounding loss of bone density, changes in blood lipids, and cardiac and vascular disease require further study.27... [Pg.1314]

Successful coadministration of bisphosphonates with the aro-matase inhibitors has been accomplished in many patients in the metastatic setting. The three available aromatase inhibitors are exemestane, anastrozole, and letrozole. [Pg.1315]

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