| Anti-androgens such as Casodex that are 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 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 towards 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 through natural selection.; We have demonstrated that the progression towards metastatic hormone-refractory disease is a 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; upregulation of extracellular matrix (ECM) protease expression; and the upregulation of stromal-mediated growth factor signaling pathways.; This also suggests that the use of anti-androgen in prostate cancer therapies are bound to fail so long as they only targets adenocarcinoma cells in the tumor while ignoring the influence of the microenvironment of the prostate tumor. This highlights the urgent need for the identification of new drug target for prostate cancer treatment that leads to less adverse size effects and avoids the increase in tumor burden later in life. |
