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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Endocrinology and Metabolic Medicine and Sterix Ltd., Faculty of Medicine, Imperial College, St. Mary's Hospital; 2 Cancer Research UK Laboratories, Department of Cancer Medicine, Hammersmith Hospital; 3 Drug Development Office, Cancer Research UK; 4 Statistical Advisory Service, Imperial College, London, United Kingdom; 5 Medicinal Chemistry and Sterix Ltd., Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom; 6 Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom; 7 Reproductive Endocrine Research Laboratory, University of Southern California Keck School of Medicine, Women's and Children's Hospital, Los Angeles, California; and 8 Cancer Research UK Formulation Unit, Department of Pharmaceutical Sciences, University of Strathclyde, Royal College Building, Glasgow, United Kingdom
Requests for reprints: Michael J. Reed, Endocrinology and Metabolic Medicine, Imperial College, St. Mary's Hospital, London W2 1NY, United Kingdom. Phone: 44-20-7886-1738; Fax: 44-20-7886-1790; E-mail: m.reed{at}imperial.ac.uk.
Purpose: 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.
Experimental Design: STX64 (667 Coumate), a tricylic coumarin-based sulfamate that irreversibly inhibits STS activity, was selected for entry into the first phase I trial of a STS inhibitor in postmenopausal women with breast cancer. STX64 was administered orally (nine patients at 5 mg and five patients at 20 mg) as an initial dose followed 1 week later by 3 x 2 weekly cycles, with each cycle comprising daily dosing for 5 days followed by 9 days off treatment. Blood and tumor tissue samples were collected for the assessment of STS activity and serum was obtained for steroid hormone measurements before and after treatment.
Results: The median inhibition of STS activity by STX64 was 98% in peripheral blood lymphocytes (PBL) and 99% in breast tumor tissue at the end of the 5-day dosing period. As expected, serum concentrations of estrone, estradiol, androstenediol, and DHEA all decreased significantly from pretreatment levels. Unexpectedly, androstenedione and testosterone concentrations also decreased. Four patients, all of whom had previously progressed on aromatase inhibitors, showed evidence of stable disease for 2.75 to 7 months. The drug was well tolerated with only minor drug-related adverse events recorded.
Conclusion: STX64 is a potent, well-tolerated STS inhibitor. It inhibits STS activity in PBLs and tumor tissues and causes significant decreases in serum concentrations of steroids with estrogenic properties.
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