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 1 ) 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.

Letrozole induces hepatotoxicity without causing oxidative stress: the protective effect of melatonin

“…The manufacturer has notified that LTZ can worsen hepatic function tests. Hepatic impairment can markedly increase the half-life of LTZ, and caution is required in such patients [31]. We have demonstrated that LTZ increased hepatic enzyme levels and induced hepatotoxicity.…”

Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4′-methanol-bisbenzonitrile in vitro

“…First, of all the AIs, letrozole is the most potent inhibitor of aromatase by tightly binding to the hem iron of the enzyme complex [12], and it may do so the same with other CYPs involved in human drug metabolism [13]. Second, anastrozole, another nonsteroidal triazole AI, has been shown to inhibit CYP1A2, 2C9, and 3A in vitro, although the K i values (8–10 μM) were much higher than the therapeutic plasma concentration of the drug and the nanomolar concentration needed to inhibit human aromatase (IC 50 = ∼15 nM) [14].…”

A bovine model for examining the effects of an aromatase inhibitor on ovarian function in women

“…Letrozole is a nonsteroidal inhibitor that inactivates the aromatase enzyme responsible for the synthesis of estrogens by reversibly binding to the heme group of this member of the cytochrome P450 enzymes (1). Aromatase inhibitors have been used as an adjuvant or first-line treatment for hormone-dependent breast cancer in postmenopausal women (2,3).…”