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Inhibition of Estrone Sulfatase Activity by Estrone-3-methylthiophosphonate: A Potential Therapeutic Agent in Breast Cancer¹

Unit of Metabolic Medicine, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London W2 1PG [L. D., A. P, M. J. R.], and School of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, Avon BA2 7AY [N. M. H., B. V. L. P], United Kingdom

² To whom requests for reprints should be addressed, at Unit of Metabolic Medicine, St. Mary's Hospital Medical School, London W2 1PG, United Kingdom.

Many breast tumors are hormone dependent, and there is evidence that hydrolysis of estrone sulfate (E₁S) to estrone, by estrone sulfatase, is an important source of the estrogen which is found in tumors. In this study, we have developed a novel pathway for the synthesis of estrone-3-methylthiophosphonate (E₁-3-MTP) and examined its ability to inhibit estrone sulfatase activity in MCF-7 breast cancer cells and human placental and breast tumor preparations. In MCF-7 breast cancer cells, E₁-3-MTP, 100 nM and 10 µM, inhibited estrone sulfatase activity by 52 and >98%, respectively. The apparent K_m and V_max for E₁S were 4.8 µM and 148 pmol/min/mg for placental and 16.9 µM and 38 pmol/min/mg for breast tumor preparations. Kinetic studies revealed that E₁-3-MTP inhibited estrone sulfatase in a competitive manner with the K_i values for placental and tumor preparations being 14.6 and 32.8 ÉM, respectively. A comparison of the metabolism of [³H]E₁S and [³H]E₁3-MTP by human placenta or rat liver revealed that, whereas 50–60% of [³H]E₁S was converted to [³H]estrone, <3% of [³H]E₁-3-MTP was hydrolyzed. The development of an efficient inhibitor of estrone sulfatase, which is resistant to metabolism, will allow the importance of the estrone sulfatase pathway of estrogen formation in breast tumors to be assessed and such an inhibitor may have considerable potential as a therapeutic agent.

¹ This study was supported by grants from 3i Research Exploitation Ltd. and Imperial College Exploitation Ltd. B. V. L. P. is a Lister Institute Fellow.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/10/92. Accepted 11/ 3/92.

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