AROMATASE INHIBITORS AS POTENTIAL CANCER CHEMOPREVENTIVES

Epidemiological and experimental evidence strongly supports a role for estrogens in the development and growth of breast tumors. A role for estrogen in prostate neoplasia has also been postulated. Therefore, on e chemopreventive strategy for breast and prostate cancers is to decre ase estrogen production. This can be accomplished by inhibiting aromat ase, the enzyme that catalyzes the final, rate-limiting step in estrog en biosynthesis. The use of aromatase inhibitors is of clinical intere st for cancer therapy, and selective, potent aromatase inhibitors have been developed. Several of these agents have demonstrated chemopreven tive efficacy in animal models. The rationale for the use of aromatase inhibitors as chemopreventives and identification of inhibitors to se rve as potential chemopreventive agents are the subjects of this revie w. After background information regarding aromatase is presented, the data for each inhibitor are summarized separately. The discussion focu ses on those inhibitors that are clinically available or in clinical t rials, including: aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole hydrochloride, anastrozole (Arimidex), letro zole, vorozole, formestane, exemestane, and atamestane. On the basis o f results from preclinical studies, aromatase inhibitors may be promis ing agents for clinical trials in populations at high risk for develop ing estrogen-dependent cancers. Total suppression of aromatase may hav e adverse effects, as is evident in postmenopausal women (increased os teoporosis, cardiovascular disease, and urogenital atrophy). However, on the basis of preclinical studies of chemopreventive efficacy and ch emotherapeutic applications of aromatase inhibitors showing dose-respo nse efficacy, it may be possible to obtain chemopreventive effects wit hout total suppression of aromatase and circulating estrogen levels. S uppressing local estrogen production may be an alternative strategy, a s suggested by the discovery of a unique transcriptional promoter of a romatase gene expression, I.4, in breast adipose tissue. The developme nt of drugs that target this promoter region may be possible.