A New Therapeutic Strategy against Hormone-Dependent Breast Cancer: The Preclinical Development of a Dual Aromatase and Sulfatase Inhibitor

• Published in: Clinical cancer research 2008-10, Vol.14 (20), p.6469-6477
• Main Authors: FOSTER, Paul A, CHANDER, Surinder K, PUROHIT, Atul, NEWMAN, Simon P, WOO, L. W. Lawrence, SUTCLIFFE, Oliver B, BUBERT, Christian, DUJIN ZHOU, SHIUAN CHEN, POTTER, Barry V. L, REED, Michael J
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic agents; Aromatase; Aromatase Inhibitors - therapeutic use; Azasteroids - therapeutic use; Biological and medical sciences; breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - surgery; Cell Proliferation - drug effects; estrogen; Estrogens - blood; Female; Gynecology. Andrology. Obstetrics; Humans; letrozole; Mammary gland diseases; MCF-7; Medical sciences; Mice; Mice, Nude; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - enzymology; Neoplasms, Hormone-Dependent - surgery; Nitriles - therapeutic use; Ovariectomy; Pharmacology. Drug treatments; Rats; Rats, Wistar; Steryl-Sulfatase - antagonists & inhibitors; Steryl-Sulfatase - metabolism; sulfatase; Treatment Outcome; Triazoles - therapeutic use; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-1027

Purpose: 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. Experimental Design: 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-7 AROM ) or STS cDNA (MCF-7 STS ) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of either androstenedione (A 4 ) or E2 sulfate and bearing either MCF-7 AROM or MCF-7 STS tumors were orally treated with STX64, letrozole, or STX681. Treatment was administered for 28 days. Mice were weighed and tumor measurements were taken weekly. Results: STX64, a potent STS inhibitor, completely blocked MCF-7 STS tumor growth but failed to attenuate MCF-7 AROM tumor growth. In contrast, letrozole inhibited MCF-7 AROM tumors but had no effect on MCF-7 STS 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. Conclusions: 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.