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

Abstract

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.

Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5α-dihydrotestosterone

“…Groups 2 and 4 received a subcutaneous injection of 4-OHA (4-androsten-4-ol-3, 17-dione; Steraloids, Newport, RI) dissolved in corn oil (5 mg/kg body wt) just before resuscitation. The dosage regime of 4-OHA employed was based on previous in vitro studies, the treatment regime for patients with prostatic and breast cancer, and previous work by our laboratory (17,32,46). No deleterious side effects of subcutaneous 4-OHA administrations at this dose were observed in the present study.…”

Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: Implications in atherosclerosis

“…2). The concentration of anastrozole selected was based on studies by other investigators who demonstrated significant aromatase inhibition in vitro at this concentration (18). Anastrozole was added 60 min before the addition of testosterone.…”

Drug Approval Summaries: Arsenic Trioxide, Tamoxifen Citrate, Anastrazole, Paclitaxel, Bexarotene

“…In postmenopausal women, Arimidex, at a daily dose of 1 mg, produced estradiol suppression of greater than 80%. Arimidex does not possess progestogenic, androgenic, or estrogenic activity [14][15][16].…”