Grant Number:	5R03CA085435-02 Interpret this number
Primary Investigator:	Imperato-Mc Ginley, Julianne
Organization:	Weill Medical College Of Cornell Univ
Project Title:	Androgens Regulate Igf Pathway and Prostate Diseases
Fiscal Year:	2001

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 following categories: I: 46 XY subjects with unique inherited conditions affecting androgen action. 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 cancer. 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 treatment. B) Prostatic cancer cells treated with either control vehicle, testosterone, DHT, testosterone plus 5alpha-reductase inhibitors, and DHT plus 50:-reductase inhibitors.





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