History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target

Abstract

Aromatase is the enzyme that catalyzes the conversion of androgens to estrogens. Initial studies of its enzymatic activity and function took place in an environment focused on estrogen as a component of the birth control pill. At an early stage, investigators recognized that inhibition of this enzyme could have major practical applications for treatment of hormone-dependent breast cancer, alterations of ovarian and endometrial function, and treatment of benign disorders such as gynecomastia. Two general approaches ultimately led to the development of potent and selective aromatase inhibitors. One targeted the enzyme using analogs of natural steroidal substrates to work out the relationships between structure and function. The other approach initially sought to block adrenal function as a treatment for breast cancer but led to the serendipitous finding that a nonsteroidal P450 steroidogenesis inhibitor, aminoglutethimide, served as a potent but nonselective aromatase inhibitor. Proof of the therapeutic concept of aromatase inhibition involved a variety of studies with aminoglutethimide and the selective steroidal inhibitor, formestane. The requirement for even more potent and selective inhibitors led to intensive molecular studies to identify the structure of aromatase, to development of high-sensitivity estrogen assays, and to "mega" clinical trials of the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, which are now in clinical use in breast cancer. During these studies, unexpected findings led investigators to appreciate the important role of estrogens in males as well as in females and in multiple organs, particularly the bone and brain. These studies identified the important regulatory properties of aromatase acting in an autocrine, paracrine, intracrine, neurocrine, and juxtacrine fashion and the organ-specific enhancers and promoters controlling its transcription. The saga of these studies of aromatase and the ultimate utilization of inhibitors as highly effective treatments of breast cancer and for use in reproductive disorders serves as the basis for this first Endocrine Reviews history manuscript.

Aromatase inhibitors of the third generation in endocrine therapy of breast cancer and endometrial cancer: the successes and failures of the combination therapy

“…Так, объективный от-вет после применения аминоглютетимида был по-лучен у 4 из 18 женщин с распространенным раком эндометрия. Однако выраженные нежелательные побочные эффекты в виде вялости, тошноты, кож-ной сыпи и лихорадки ограничили клиническое использование препарата, к тому же аминоглю-тетимид не полностью ингибировал ароматазную активность [14].…”

Antiproliferative and antibacterial activity of some glutarimide derivatives

“…Lenalidomid has been used for the treatment of multiple myeloma, while pomalidomid has been recently approved by FDA for the treatment of relapsed and refractory multiple myeloma 22 . Some estrone derivatives with the D-ring replaced with the glutarimide moiety showed potent inhibition of steroid sulfatase, an enzyme involved in the pathway of the development of hormone-dependent breast tumors 23 ; while aminoglutethimide, the non-steroidal aromatase inhibitor, is in use for the treatment of hormone-sensitive metastatic breast cancer 24,25 . In the past decade, antitumor activity in vitro of mitonafide 26 , amonafide 27 and naphthalimide 28,29 derivatives was intensively examined.…”

Identification of CYP19A1 single-nucleotide polymorphisms and their haplotype distributions in a Korean population

“…9 One of the important features of aromatase is evidenced by the fact that selective aromatase inhibitors are increasingly used to treat postmenopausal women with estrogen-responsive breast cancer. 10 Therefore, CYP19A1 coding for aromatase has been an attractive target for identification of common genetic polymorphisms that may account for different levels of estrogen in humans. However, no efforts to resequence the CYP19A1 gene for a Korean population have been made.…”