Abstract
The anti‐androgens used in prostate cancer therapy have been designed to interfere with the normal androgen receptor (AR)‐mediated processes that ensure prostate cell survival, triggering tumor cells to undergo programmed cell death. While anti‐androgens were originally designed to treat advanced disease, they have recently been used to debulk organ‐confined prostate tumors, to improve positive margins prior to surgery, and for chemoprevention in patients at high risk for prostate cancer. However, tumors treated with anti‐androgens frequently become hormone refractory and acquire a more aggressive phenotype. Progression toward metastatic hormone‐refractory disease has often been regarded as the outgrowth of a small number of hormone‐independent cells that emerge from a hormone‐dependent tumor during anti‐androgen treatment by natural selection. While a number of selective advantages have recently been identified, there is also considerable evidence suggesting that the progression toward metastatic hormone‐refractory disease is an dynamic process which involves abrogation of programmed cell death as a result of the attenuation of DNA fragmentation and maintenance of mitochondrial membrane potential in tumor cells; the upregulation of stromal‐mediated growth factor signaling pathways; and the upregulation of extracellular matrix (ECM) protease expression. © 2004 Wiley‐Liss, Inc.