Aromatase Inhibitors

Abstract

Aromatase is the enzyme synthesizing estrogens from androgens. In estrogen-dependent breast tumors, estrogens induce the expression of growth factors responsible for cancer cell proliferation. In situ estrogen synthesis by aromatase "is thought to play a key role in the promotion of breast cancer growth. Aromatase inhibitors (AIs) provide new approaches for the prevention and treatment of breast cancer by inhibiting estrogen biosynthesis. Through reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical techniques, aromatase has been found to be expressed in many endocrine tissues and tumors originating from these tissues. Unexpectedly, this enzyme is now known to also be expressed in liver, lung, and colon cancers. Such findings suggest a potential role for endocrine manipulation of these types of cancer using AIs. Three Food and Drug Administration (FDA)-approved AIs, anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin), effectively challenging tamoxifen, have been used as first-line drugs in the treatment of hormone-dependent breast cancer, and possibly other aromatase-expressing cancers. In addition, natural anti-aromatase chemicals, such as flavones and coumarins, have been identified. Efforts to develop new lines of AIs derived from these phytochemicals have been initiated in several laboratories. Finally, significant progress has been made in the understanding of the structure-function relationship of aromatase. Such information has helped the examination of binding characteristics of AIs, the evaluation of reaction mechanism of aromatase, and the explanation of the molecular basis for a low catalytic activity of the natural variant, M364T.

A Comparison of the Efficacy of Two Doses of Letrozole Alone or with Continuous Recombinant Follicle-Stimulating Hormone for Ovulation Induction in Anovulatory Women

“…Aromatase is the key enzyme that converts testosterone to estradiol (E 2 ) [1]. The concept of using aromatase inhibitors (AIs) as a new method of controlled ovarian stimulation has been extensively investigated by several research groups in the past few years [2,3,4,5].…”

New experimental models for aromatase inhibitor resistance

“…M364 faces inside the active site, although it is not close to the heme and steroidal ligand. It is likely that M364 helps to form the hydrophobic pocket together with the loop P368-M374 [20]. Overall, our structure-function studies offer new information regarding interactions between aromatase and its inhibitors, and we provide new evidence that further delineates between steroidal and non-steroidal aromatase inhibitor functionality.…”

“…2). It is thought that the side chain of R365 forms a hydrogen bond with the backbone carbonyl oxygen of P410, which is located in the loop between the β-1/β-2 sheets (R375-I395) and L helix (G439-R456) [20]. C437, the heme-binding cysteine residue, is located at the end of this loop.…”

Aromatase inhibitors for breast cancer: different structures, same effects?

“…Type I AIs bind covalently to the enzyme causing its irreversible inactivation, while the non-steroidal compounds are characterised by reversible binding. First-generation (testolactone, aminoglutethimide) and second-generation (formestane, fadrozole) compounds of both the classes are characterised by lower selectivity and potency when compared with the newer AIs (exemestane, anastrozole and letrozole; Hong & Chen 2006).…”