@Article{,
AUTHOR = {Eric A. Singer, Dragan J. Golijanin, Edward M. Messing},
TITLE = {Androgen deprivation therapy for advanced prostate cancer: why does it fail and can its effects be prolonged?},
JOURNAL = {Canadian Journal of Urology},
VOLUME = {15},
YEAR = {2008},
NUMBER = {6},
PAGES = {4381--4387},
URL = {http://www.techscience.com/CJU/v15n6/62238},
ISSN = {1488-5581},
ABSTRACT = {Androgen deprivation therapy (ADT) has been the 
cornerstone of treatment for advanced prostate cancer 
for over 65 years. Although there can be worrisome 
side effects, data will be presented that for men with 
metastatic prostate cancer, immediate ADT can reduce 
the likelihood of developing the rare but catastrophic 
sequellae of metastatic disease, although it is unlikely 
to prolong survival compared with waiting for 
symptoms before initiating ADT. Additionally, for 
patients with extremely high risk prostate cancer that 
is not distantly metastatic (e.g. have a life expectancy 
from prostate cancer less than 10 years with all other 
available treatments except immediate ADT) and, 
whose life expectancy from non-prostate cancer diseases 
is excellent during this period, early ADT both alone 
and in conjunction with definitive local treatment 
prolongs survival. Moreover, ADT seems to be most 
effective when the cancer volume is low. However, 
eventually most men receiving ADT experience disease 
progression.<br/>
The biological mechanisms explaining how prostate cancer 
escapes from ADT’s control include: <br/>
1) Alterations in the androgen receptor (AR) and in the 
AR co-factors (which modify the responsiveness of the AR 
to androgens) allow molecules and medications which are 
not normally AR agonists to act as agonists.<br/>
2) The human prostate gland, and particularly prostate 
cancer, may be able to synthesize androgens from both 
cholesterol and adrenal androgens. This may occur 
because prostate cancer tissue has higher concentrations 
of androgens than does the serum in patients receiving 
ADT. Thus, castrated men may not be starving their 
prostate cancers of androgens.<br/>
3) The AR in prostatic stroma far more strongly stimulates 
both malignant and benign prostatic epithelial growth than 
the epithelial AR does. Indeed, the epithelial AR, particularly 
in advanced prostate cancer, may have anti-proliferative and 
anti-tumor progression properties. That is, the AR in the 
prostatic epithelial cells, particularly malignant ones, may 
act as a tumor suppressor. Thus, by inhibiting the epithelial 
AR, its protective effects may be abrogated.<br/>
The controversial nature of these concepts, as well as the 
clinical and experimental data which support and question 
them, will be presented. Additionally, strategies for 
addressing each of these escape mechanisms, which may be 
able to prolong responsiveness to ADT, will be discussed.},
DOI = {}
}