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The Role of 17ß-Hydroxysteroid Dehydrogenases in Modulating the Activity of 2-Methoxyestradiol in Breast Cancer Cells

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

Requests for reprints: Simon P. Newman, Endocrinology and Metabolic Medicine, Faculty of Medicine, Imperial College, St Mary's Hospital, London W2 1NY, United Kingdom. Phone: 44-207-886-1210; Fax: 44-207-886-1790; E-mail: simon.newman{at}imperial.ac.uk.

The bis-sulfamoylated derivative of 2-methoxyestradiol (2-MeOE2), 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE), has shown potent antiproliferative and antiangiogenic activity in vitro and inhibits tumor growth in vivo. 2-MeOE2bisMATE is bioavailable, in contrast to 2-MeOE2 that has poor bioavailability. In this study, we have examined the role of 17ß-hydroxysteroid dehydrogenase (17ß-HSD) type 2 in the metabolism of 2-MeOE2. In MDA-MB-231 cells, which express high levels of 17ß-HSD type 2, and in MCF-7 cells transfected with 17ß-HSD type 2, high-performance liquid chromatography analysis showed that a significant proportion of 2-MeOE2 was metabolized to inactive 2-methoxyestrone. Furthermore, MCF-7 cells transfected with 17ß-HSD type 2 were protected from the cytotoxic effects of 2-MeOE2. In contrast, no significant metabolism of 2-MeOE2bisMATE was detected in transfected cells and 17ß-HSD type 2 transfection did not offer protection against 2-MeOE2bisMATE cytotoxicity. This study may go some way to explaining the poor bioavailability of 2-MeOE2, as the gastrointestinal mucosa expresses high levels of 17ß-HSD type 2. In addition, this study shows the value of synthesizing sulfamoylated derivatives of 2-MeOE2 with C17-position modifications as these compounds have improved bioavailability and potency both in vitro and in vivo. (Cancer Res 2006; 66(1): 324-30)

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