A new therapeutic strategy against hormone-dependent breast cancer: the preclinical development of a dual aromatase and sulfatase inhibitor

The production of E2 is paramount for the growth of estrogen receptor-positive breast cancer. Various strategies have been used, including the use of enzyme inhibitors against either aromatase (AROM) or steroid sulfatase (STS), in an attempt to ablate E2 levels. Both these enzymes play a critical role in the formation of estrogenic steroids and their inhibitors are now showing success in the clinic. We show here, in a xenograft nude mouse model, that the inhibition of both enzymes using STX681, a dual AROM and STS inhibitor (DASI), is a potential new therapeutic strategy against HDBC. MCF-7 cells stably expressing either AROM cDNA (MCF-7AROM) or STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of either androstenedione (A4) or E2 sulfate and bearing either MCF-7AROM or MCF-7STS tumors were orally treated with STX64, letrozole, or STX681. Treatment was administered for 28 days. Mice were weighed and tumor measurements were taken weekly. STX64, a potent STS inhibitor, completely blocked MCF-7STS tumor growth but failed to attenuate MCF-7AROM tumor growth. In contrast, letrozole inhibited MCF-7AROM tumors but had no effect on MCF-7STS tumors. STX681 completely inhibited the growth of both tumors. AROM and STS activity was also completely inhibited by STX681, which was accompanied by a significant reduction in plasma E2 levels. This study indicates that targeting both the AROM and the STS enzyme with a DASI inhibits HDBC growth and is therefore a potentially novel treatment for this malignancy

Phase I study of STX 64 (667 Coumate) in Breast Cancer Patients: the First Study of a Steroid Sulphatase Inhibitor

Inhibition of steroid sulfatase (STS), the enzyme responsible for the hydrolysis of steroid sulfates, represents a potential novel treatment for postmenopausal women with hormone-dependent breast cancer. Estrone and DHEA are formed by this sulfatase pathway and can be converted to steroids (estradiol and androstenediol, respectively), which have potent estrogenic properties

Lipolytic enzymes and hydrolytic rancidity

Lipolysis, the enzymic hydrolysis of milk lipids to free fatty acids and partial glycerides, is a constant concern to the dairy industry because of the detrimental effcts it can have on the flvor and other properties of milk and milk products. However, free fatty acids also contribute to the desirable flavor of milk and milk products when present at low concentrations and, in some cheeses, when present at high concentrations. The enzymes responsible for the detrimental effects of lipolysis are of two main types: those indigenous to milk, and those of microbial origin. The major indigenous milk enzyme is lipoprotein lipase. It is active on the fat in natural milk fat globules only after their disruption by physical treatments or if certain blood serum lipoproteins are present. The major microbial lipases are produced by psychrotrophic bacteria. Many of these enzymes are heat stable and are particularly significant in stored products. Human milk differs from cows' milk in that it contains two lipases, a lipoprotein lipase and a bile salt-stimulated lipase. The ability of the latter to cause considerable hydrolysis of ingested milk lipids has important nutritional implications