This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Newman, S. P. Articles by Purohit, A. Search for Related Content PubMed PubMed Citation Articles by Newman, S. P. Articles by Purohit, A.

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)

This article has been cited by other articles:

				S. P. Newman, P. A. Foster, C. Stengel, J. M. Day, Y. T. Ho, J.-G. Judde, M. Lassalle, G. Prevost, M. P. Leese, B. V.L. Potter, et al. STX140 Is Efficacious In vitro and In vivo in Taxane-Resistant Breast Carcinoma Cells Clin. Cancer Res., January 15, 2008; 14(2): 597 - 606. [Abstract] [Full Text] [PDF]