The discovery and mechanism of action of letrozole

Abstract

Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole (Femara) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women.

Fig. 1

Aromatization of androgens to estrogens in postmenopausal women. A androstenedione, E1 estrone, E1S estrone sulfate, E2 estradiol, T testosterone. Reprinted from [38] with permission from the Society of Endocrinology

Fig. 2

The development of aromatase inhibitors (AIs) has culminated in agents with high specificity and potency for aromatase. Spectrum of action of first- through third-generation AIs: The third-generation AIs act exclusively on the aromatase enzyme and do not appear to exert additional effects. Potency of AIs determined by degree of inhibition of total body aromatase: 4-OHA 4-hydroxyandrostenedione. Reprinted from [66] with permission from the Society of Endocrinology

Fig. 3

Comparison of the molecular structures of aromatase inhibitors. Reprinted from [77] with permission from Elsevier

Fig. 4

Relative potencies with which letrozole, anastrozole, and fadrozole inhibit aromatase from non-cellular and intracellular sources. Reprinted from [31] with permission from Elsevier