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¹ Department of Surgery, Division of Urology, University of Massachusetts Medical School, Worcester, Massachusetts and ² Department of Chemistry, College of Arts and Sciences, Northeastern University, Boston, Massachusetts

Requests for Reprints: Shuk-Mei Ho, Department of Surgery, Division of Urology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-2324. Phone: (508) 856-1909; Fax: (508) 856-8699. E-mail: shuk-mei.ho{at}umassmed.edu

Prostate cancer remains the number one cause of noncutaneous cancer, with 220,900 new cases predicted for the year 2003 alone. Of the more promising classes of compounds studied thus far for the treatment of prostate cancer, estrogens of various types have consistently exhibited antitumor activities both in vitro and in vivo. For this reason, we have synthesized and screened a library of unique 17/11ß modified 17ß-estradiol (E₂) analogues designed for estrogen receptor ß (ER-ß) specificity and a potential for cytotoxic activity directed toward prostate cancer cells. From this library, the novel compound 17-20Z-21-[(4-amino)phenyl]-19-norpregna-1,3,5(10),20-tetraene-3,17ß-diol (APVE₂) was identified as the primary lead, found to induce a high level (>90%) of cell death through an apoptotic mechanism, with an EC₅₀ of 1.4, 2.7, and 16 nM in the LNCaP, PC3, and DU145 cell lines, respectively. APVE₂ was found to bind to ER-ß, albeit weakly, with an EC₅₀ of 250 nM and a binding activity of 6.2% relative to E₂, nearly two orders of magnitude less than the concentration required to induce apoptosis. APVE₂ bound preferentially to ER-ß by 7-fold over ER-, and did not induce growth in the MCF-7 cell line, thus indicating that it is not a classical ER agonist. Furthermore, the cytotoxic actions of APVE₂ were not reversed by co-treatment with a 50-fold excess E₂. In summary, a novel 17 modified estrogen APVE₂ was identified as a lead compound, capable of inducing apoptosis in three prostate cancer cell lines at low nanomolar concentrations, through a mechanism inconsistent with an ER-mediated mechanism.

Key Words: Anti-estrogens • Apoptosis • Estrogen receptor • Hormone therapy • Novel therapeutics • Prostate cancer • Recurrent disease

Grant support: NIH (DK61084) and US Army Prostate Research Program (DAMD17-98-1-8606) (S-M. Ho), NIH (CA81049) (R.H. Hanson), and Grant Number 5 P30 DK32520 from the National Institute of Diabetes and Digestive and Kidney Diseases.

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.

Note: J.A. Mobley and J.O. L'Esperance contributed equally to this work.

³ Unpublished data.

Received 9/ 8/03; revised 2/17/04; accepted 2/26/04.