Exemestane (FCE 24304), A new steroidal aromatase inhibitor

Salle, E. Di; Ornati, G.; Giudici, D.; Lassus, M.; Evans, T.R. Jeffry; Coombes, R. Charles

doi:10.1016/0960-0760(92)90198-r

Cited by 84 publications

(42 citation statements)

References 34 publications

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“…This is most readily shown in vitro, aromatase activity being effectively inhibited in both particulate fractions of breast cancers and cultures of mammary adipose tissue fibroblasts. The sensitivity to individual inhibitors in these systems is similar to that previously reported in placental microsomes (di Salle et al 1992, Plourde et al 1994, with the newer inhibitors being at least 100-fold more potent than aminoglutethimide and having IC 50 values at nM concentrations (compared with µM values for the older drug). Some differences between test systems were noted.…”

Section: Discussionsupporting

confidence: 63%

Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.

Miller

1999

Endocrine-Related Cancer

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Both mammary adipose tissue and breast cancers have the ability to aromatize androgens into oestrogens. Such potential may maintain the growth of hormone-dependent tumours. It has therefore been important to determine the effects of new aromatase inhibitors such as formestane, exemestane, anastrozole and letrozole on oestrogen biosynthesis and concentrations of endogenous hormones within the breast. Studies based on in vitro incubations of breast cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these drugs are highly effective inhibitors, with IC 50 values ranging between 1 and 50 nM (although the relative efficacy varies between tissues and test systems). Despite this potential, in vitro incubations of breast tissues from patients treated with type II inhibitors such as aminoglutethimide and letrozole can display paradoxically high aromatase activity; this appears to be caused by the reversible nature of the inhibition, coupled with induction/stabilization of the aromatase enzyme. To assess in situ effects within the breast, postmenopausal women with large primary breast cancers have been treated neoadjuvantly with aromatase inhibitors using a protocol that included (i) breast biopsy before treatment, (ii) definitive surgery after 3 months of treatment and (iii) infusion of [ 3 H]androstenedione and [14 C]oestrone in the 18 h immediately before biopsy and surgery. With this study design, it has been shown that drugs such as letrozole profoundly inhibit in Endocrine-Related Cancer (1999) 6 187-195 situ aromatase activity and reduce endogenous oestrogens within the breast.

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Section: Discussionsupporting

confidence: 63%

Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.

Miller

1999

Endocrine-Related Cancer

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“…Exemestane has a very low binding affinity for the androgen receptor in vitro (0.22%) and a marginal androgenic activity in vivo as demonstrated in castrated male rats (1% of the activity of testosterone propionate) [38]. It is unlikely that such marginal effects may explain the growth inhibition observed.…”

Section: Discussionmentioning

confidence: 99%

Impaired Body Weight and Tail Length Gain and Altered Bone Quality after Treatment with the Aromatase Inhibitor Exemestane in Male Rats

et al. 2010

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Background: Estrogen deficiency induced by aromatase inhibitors may be a novel treatment modality for growth enhancement in short children, but may have adverse effects on bone, brain and reproduction. Aim: To assess growth effects and potential adverse effects of aromatase inhibition in male rats. Methods: 26-day-old prepubertal rats received intramuscular injections with placebo or the aromatase inhibitor exemestane at a dose of 10, 30 or 100 mg/kg/week [E10, E30, E100(6)] for 6 weeks, completely covering the sexual maturation phase, or with 3 weeks E100 followed by 3 weeks placebo [E100(3)]. Growth parameters and histology of the testis, seminal vesicle and brain were analyzed. Bone architecture was studied with X-ray microtomography. Results: Exemestane dose-dependently decreased body weight and tail length gain, as well as liver and seminal vesicle weights, but did not affect nose-anus length gain, growth plate width or radial growth. E100(6) decreased trabecular thickness (epiphysis and metaphysis) and number (metaphysis). Normal IGF-I levels and brain, testis and seminal vesicle morphology were observed. E100(3) resulted in decreased tail length gain only. Conclusion: Exemestane treatment during sexual maturation did not augment linear growth in male rats, but caused impaired body weight and tail length gain and osteopenia.

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“…It binds irreversibly with aromatase leading to loss of activity. However, this compound and its metabolite, 17-hydroxyexemestane in particular, have the potential for androgenic effects via their binding to the androgen receptor [14,15].…”

Section: Mechanism Of Action Of Aromatase Inhibitorsmentioning

confidence: 99%

Aromatase inhibitor-induced arthralgia in early breast cancer: what do we know and how can we find out more?

Din

Dodwell

Wakefield

et al. 2010

Breast Cancer Res Treat

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Aromatase inhibitors (AIs) are a standard of care for the adjuvant treatment of hormone responsive early carcinoma of the breast as demonstrated in a number of large international phase III randomised trials. Arthralgia was a somewhat unexpected side effect of this class of agents and has proven to be potentially problematic in clinical practice. Although rates of up 35% have been reported in the randomised trials, the figure has been much higher in subsequent case series. There is concern that these symptoms are significant and may affect compliance and thus the overall efficacy of treatment. It is therefore extremely important that we evaluate this syndrome with a view to gaining more information regarding its clinical features and possible aetiological mechanism. The potential aetiological mechanisms and evidence for aromatase inhibitor-induced arthralgia (AIA) are reviewed in this article. Looking forward, it is now important that prospective clinical trials are well designed to evaluate this syndrome and potential therapeutic strategies to circumvent it. Radiological imaging and biochemical analyses may help our understanding of AIA and these are discussed.

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Exemestane (FCE 24304), A new steroidal aromatase inhibitor

Cited by 84 publications

References 34 publications

Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.

Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.

Impaired Body Weight and Tail Length Gain and Altered Bone Quality after Treatment with the Aromatase Inhibitor Exemestane in Male Rats

Aromatase inhibitor-induced arthralgia in early breast cancer: what do we know and how can we find out more?

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