Disclosure summary: The authors have nothing to declare.
Effects of steroidal and non-steroidal antiandrogens on wild-type and mutant androgen receptors†
Article first published online: 20 MAR 2007
Copyright © 2007 Wiley-Liss, Inc.
Volume 67, Issue 8, pages 799–807, 1 June 2007
How to Cite
Urushibara, M., Ishioka, J., Hyochi, N., Kihara, K., Hara, S., Singh, P., Isaacs, J. T. and Kageyama, Y. (2007), Effects of steroidal and non-steroidal antiandrogens on wild-type and mutant androgen receptors. Prostate, 67: 799–807. doi: 10.1002/pros.20542
- Issue published online: 23 APR 2007
- Article first published online: 20 MAR 2007
- Manuscript Accepted: 6 NOV 2006
- Manuscript Received: 18 OCT 2006
- Ministry of Education, Science and Culture, Japan. Grant Numbers: 17591666, 17591667
- prostate neoplasms;
- androgen antagonists
Molecular basis for secondary antiandrogen therapy in prostate cancer with mutant androgen receptors (ARs) is not fully elucidated.
MATERIALS AND METHODS
Effects of steroidal and non-steroidal antiandrogens on transcriptional activities of wild-type and mutant (W741C, T877A, and W741C+T877A) ARs were measured. Crystal structure analysis and docking studies were performed using Molecular Operating Environment (MOE) package.
DHT-induced transcriptional activity of the T877A mutant and the W741C mutant was suppressed by bicalutamide and hydroxyflutamide, respectively. Nilutamide suppressed the W741C mutant and the double mutant. Cyproterone acetate modestly inhibited the W741C mutant and the double mutant. The structural studies suggested that nilutamide and cyproterone acetate retain their antiandrogenic properties against both the W741C mutant and the double mutant due to fact that mutation W741C does not permit formation of key hydrophobic interaction between ligand and AR ligand binding domain, which is necessary for their conversion into agonists.
Switching antiandrogens may be reasonable in prostate cancer with mutant ARs. Prostate 67: 799–807, 2007. © 2007 Wiley-Liss, Inc.