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In vivo Efficacy of STX213, A Second-Generation Steroid Sulfatase Inhibitor, for Hormone-Dependent Breast Cancer Therapy

Authors' Affiliations: ¹ Department of Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College Faculty of Medicine, St. Mary's Hospital, London, United Kingdom and ² Medicinal Chemistry, Department of Pharmacology and Pharmacy and Sterix Ltd., University of Bath, Bath, United Kingdom

Requests for reprints: Paul A. Foster, Department of Endocrinology and Metabolic Medicine, Imperial College Faculty of Medicine, St. Mary's Hospital, London W2 1NY, United Kingdom. Phone: 44-207-886-1210; Fax: 44-207-886-1790; E-mail: paul.foster{at}imperial.ac.uk.

Purpose: Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model.

Experimental Design: MCF-7 cells stably expressing STS cDNA (MCF-7_STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7_STS and wild-type MCF-7 (MCF-7_WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly.

Results: STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7_WT and 3.8-fold for MCF-7_STS after 49 days compared with day 0. MCF-7_WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7_STS tumors, and recovery of these tumors was significantly retarded (P < 0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7_STS tumors directly correlated with the corresponding STS enzyme activity.

Conclusions: This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.

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