||5R03CA085435-02 Interpret this number
||Imperato-Mc Ginley, Julianne
||Weill Medical College Of Cornell Univ
||Androgens Regulate Igf Pathway and Prostate Diseases
DESCRIPTION (Applicant's Description) Both androgens and growth factors are
important in prostate differentiation and growth. Insulin-like growth
factors, IGF-I and TGF-II, acting through the IGF-I receptor are mitogenic and
antiapoptotic to prostate epithelial cells. Androgens and IGFs interact to
mutually potentiate their effects. Blocking conversion of testosterone to 5
alpha-dihydrotestosterone (DHT), inhibits prostatic IGF-I and IGF-I receptor
gene expression while inducing IGFBP-3 gene expression. Conversely, IGF-I
induces 5 alpha-reductase isozyme expression which converts testosterone to
DHT in tissue culture and directly activates the androgen receptor. Animal
and human studies suggest that androgens may increase circulating levels of
IGF-I as well as prostatic IGF-I, IGF-II and IGF-I receptor gene expression.
Also, circulating IGF-I levels are higher in benign prostate hyperplasia (BPH)
and prostate cancer, both androgen mediated conditions. The effect of
lowering androgens, in particular DHT, on circulating IGF-I levels is unknown.
We hypothesize that circulating IGF-1 in males is regulated by androgen which
stimulate both hepatic and prostatic IGF-1 production and that DHT is the
primary androgen responsible for this process.
To test the relationship between testosterone and DHT in regulating
circulating IGF-I levels, normal males will be compared to subjects in the
I: 46 XY subjects with unique inherited conditions affecting androgen
A) Homozygous and heterozygous males with a decrease in DHT secondary to an
inherited gene defect in 5 alpha-reductase-2.
B) 46 XY subjects with complete androgen insensitivity syndrome due to
androgen receptor mutations blocking the actions of both testosterone
and DHT at target areas.
II: Males with BPH at baseline and after treatment with placebo or the 5
alpha-reductase inhibitor finasteride to lower DHT.
III: Males who have had a prostatectomy for early organ confined prostate
We also plan to examine the androgen control of the IGF-I pathway in prostate
cancer and hypothesize that DHT is the androgen mainly responsible for
regulation. Studies include:
A) Males with metastatic prostate cancer before and after anti-androgen
B) Prostatic cancer cells treated with either control vehicle,
testosterone, DHT, testosterone plus 5alpha-reductase inhibitors, and DHT
plus 50:-reductase inhibitors.