Aromatase inhibitors

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As noticed above, the first-generation aromatase inhibitor, aminoglute-thimide, was an unsuccessful, adrenotoxic antiepileptic compound implemented for breast cancer therapy in an attempt to achieve a "medical adrenalectomy." While the drug was found to be an effective antitumor agent, meticulous work by Santen et al. identified aminoglutethimide as an aromatase inhibitor in vivo (21). Thus, despite interacting with several enzymes involved in adrenal steroid synthesis, circulating androgen levels were found preserved despite profound suppression of circulating estrogens (22). The reason why plasma androstenedione and testosterone levels were not affected (although there were changes in the ratio of several adrenal-derived hormones) was probably due to an increase in ACTH secretion (see (23) for a detailed description of the effects of aminoglutethimide on adrenal enzyme activities). The finding that amino-glutethimide caused estrogen suppression and, thus, antitumor effects through inhibiting the aromatase enzyme only, was a key milestone triggering the process subsequently leading to successful development of these new compounds in breast cancer therapy.

A second major event was the laboratory work of Harry and Angela Brodie, identifying androstenedione derivatives as potent aromatase inhibitors (24). These steroidal compounds act by irreversibly binding to the substrate-binding pocket on the aromatase enzyme (25), and have no effect on other enzymes involved in steroid disposition when given in the doses established in the clinic.

The main reason for subsequent development of second- and third-generation aromatase inhibitors were the side effects (aminoglutethimide) and inconvenience of parenteral administration (4-hydroxyandrostene-dione) of the two first compounds. For aminoglutethimide, interactions with adrenal steroid-synthesizing enzymes lead to glucocorticoid- and, sometimes, mineralocorticoid- deficiencies, required glucocorticoid substitution with or without mineralocorticoids (26). Even more important, the compound caused neurological as well as skin side effects (23). The most serious complication of aminoglutethimide was the rare finding of blood dyscracias (27). Thus, much effort was invested into developing less toxic compounds. For 4-hydroxyandrostenedione, the compound required 2-weekly intramuscular injections for optimal estrogen suppression (28), as oral administration was ineffective due to poor bioavailability of the compound (29, 30).

Due to these limitations for both compounds mentioned above, a number of more selective, less toxic compounds were developed by different pharmaceutical companies. In collaboration with Professor Dowsett's Group at the Royal Marsden Hospital, London, we developed a highly sensitive method for measurement of in vivo aromatization using a double-tracer technique (31-33). Using this system, we were able to classify different compounds based on their biochemical efficacy (Table 1); (34). Most importantly, the difference recorded was corroborated by clinical findings. While the first compounds, like fadrozole, similar to aminoglutethimide and 4-hydroxyandrostenedione caused 80-90% aromatase inhibition, these compounds were associated with reduced toxicity but did not improve antitumor efficacy (35-39). In contrast, the three so-called third-generation compounds (Fig. 2), anastrozole, letrozole, and exemestane, caused >98% in vivo inhibition (Table 1). These compounds were subsequently shown to be superior regarding clinical efficacy to conventional antihormonal therapy in metastatic breast cancer (40-44).


No other single compound has had an impact on breast cancer therapy like the first selective estrogen receptor modifier (SERM), tamoxifen. Due to its antitumor efficacy combined with a low-toxicity profile, the drug remained first-line endocrine therapy for metastatic breast cancer among pre- as well as postmenopausal women for decades (see detailed description of early and basic findings in (45), subsequently to become standard endocrine therapy in the adjuvant setting. A detailed description of the biochemical actions of tamoxifen is beyond the scope of this paper, and the readers are referred to comprehensive reviews on the subject (45-47).

The fact that tamoxifen was found of similar efficacy among pre- and postmenopausal women remains somewhat surprising. Not only do the two groups express different estrogen levels; in addition, tamoxifen was shown to elevate plasma levels of estradiol 2 to 3-fold in premenopausal women due to interaction with follicular maturation (48). A possible explanation is that the regular dose of tamoxifen, 20 mg daily, represents an "overdose"; thus, Descenci et al. have shown tamoxifen down to doses of 5 mg daily to exert effects on surrogate parameters resembling what is observed with the 20 mg daily dose (49). The relevance of such comparison is indirectly supported by the findings from a large phase III study comparing the second-generation SERM droloxifene (3-hydroxy-tamoxifene) to tamoxifen in pre- and postmenopausal women with meta-satic breast cancer (50). Here, droloxifene was found of similar antitumor efficacy to tamoxifen among postmenopausal patients but inferior for premenopausals. Notably, at the dose administered (40 mg daily), droloxifene was shown to have less effect on surrogate parameters like SHBG and the IGF-binding proteins compared to droloxifene 100 mg or tamoxifen 20-30 mg daily (51-53). These findings may be consistent with the hypothesis that tamoxifen 20 mg daily allowed the drug to block the effect even of high premenopausal estrogen concentrations in the tissue. In contrast, droloxifene (40 mg daily) was able to block estrogen

Table 1. Effects of different aromatase inhibitors and inactivators on whole-body aromatization*


Drug dose

% aromatase inhibition


250mg qid


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