Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer

American Association for the Advancement of Science (AAAS) - Tập 324 Số 5928 - Trang 787-790 - 2009
Chris Tran1, Samedy Ouk2, Nicola J. Clegg1, Yu Chen3,1, Philip A. Watson1, Vivek Arora1, John Wongvipat1, Peter Smith‐Jones4, Dongwon Yoo2, Andrew Kwon1, Teresa Wasielewska1, Derek S. Welsbie5, Charlie Degui Chen5, Celestia S. Higano6, Tomasz M. Beer7, David T. Hung8, Howard I. Scher3, Michael E. Jung2, Charles L. Sawyers9,1
1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
2Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
3Genitourinary Oncology Service, Division of Solid Tumor Oncology and Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
4Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
5Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095 USA
6Division of Oncology, Departments of Medicine and Urology, University of Washington, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
7OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
8Medivation, Inc., 201 Spear Street, San Francisco, CA 94105, USA.
9Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA

Tóm tắt

A Second Act for Antiandrogens Men with advanced prostate cancer are often treated with antiandrogens; drugs that inhibit the activity of male hormones, such as testosterone, that help drive tumor growth. Many of these drugs act by functionally disrupting the androgen receptor (AR), a transcriptional regulator of cell proliferation, but tumors eventually become resistant to the drugs by expressing higher levels of the AR. Tran et al. (p. 787 , published online 9 April) have developed a “second-generation” antiandrogen, a thiohydantoin called MDV3100, which binds the AR with high affinity. MDV3100 retains its anticancer activity in cell culture and in mouse models even when AR levels are elevated. The drug appears to act both by inhibiting translocation of the AR into the nucleus and by reducing its transcriptional activity. MDV3100 is being tested in patients with advanced prostate cancer, the first group of which have shown a decline in blood levels of a marker of cancer growth, prostate-specific antigen.

Từ khóa


Tài liệu tham khảo

10.1200/JCO.2005.03.4777

10.1002/jcb.10653

10.1038/nm972

10.1016/S0094-0143(05)70389-X

10.1016/S0092-8674(00)81717-1

10.1073/pnas.0500381102

10.1038/sj.pcan.4500262

10.1016/0960-0760(94)90257-7

10.1021/jm000163y

Larson S. M., et al.., J. Nucl. Med. 45, 366 (2004).15001675

10.1593/neo.08428

10.1158/0008-5472.CAN-05-0817

10.1158/0008-5472.CAN-06-1397

10.1159/000463972

10.1074/jbc.M408972200

10.1073/pnas.0510842103

10.1074/jbc.M203310200

10.1021/bi061321b