Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer.
OBJECTIVE
In the prostate testosterone is converted to dihydrotestosterone (DHT) by the enzymes 5alpha-reductase (5alphaR) types 1 and 2 (5alphaR1 and 5alphaR2). Suppression of DHT formation by 5alphaR inhibition may be beneficial in early treatment or prevention of prostate cancer. Although 5alphaR2 is the dominant enzyme in the prostate, evidence indicates that 5alphaR1 may be up-regulated in some prostate cancers. This suggests that dual inhibition of both isoenzymes may be more effective than suppression of 5alphaR2 alone in prostate cancer treatment or prevention. In this short-term pilot study we examined the effect of the dual 5alphaR inhibitor dutasteride on markers of tumor regression.


METHODS
A total of 46 men with clinically staged T1 or T2 prostate cancer were randomized to receive 5 mg per day of placebo or dutasteride for 6 to 10 weeks before radical prostatectomy. Resected tissues were analyzed to determine the effect of dutasteride on intraprostatic androgen levels, and indices of apoptosis and microvessel density (MVD) in malignant tissue, as well as degree of atrophy in benign tissue.


RESULTS
Treatment with dutasteride caused a 97% decrease in intraprostatic DHT and was associated with a trend toward increased apoptosis. In patients receiving dutasteride for 45 days or more, a significant increase in apoptosis and a trend toward decreased MVD in prostate cancer tissue was observed. Dutasteride treatment was also associated with an 18% decrease in mean benign epithelial cell width compared with placebo (p < 0.0001).


CONCLUSIONS
In this pilot study dutasteride treatment resulted in almost complete suppression of intraprostatic DHT, increased apoptosis and a trend toward decreased MVD. These findings suggest that short-term treatment with dutasteride can cause regression in some prostate cancers.
Andriole
G L
GL
Division of Urologic Surgery, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, USA. andrioleg@msnotes.wustl.edu
Humphrey
P
P
Ray
P
P
Gleave
M E
ME
Trachtenberg
J
J
Thomas
L N
LN
Lazier
C B
CB
Rittmaster
R S
RS
D058891:5-alpha Reductase Inhibitors; D000368:Aged; D000728:Androgens / Q000378:metabolism; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis; D001284:Atrophy; D001378:Azasteroids / Q000627:therapeutic use*; D013196:Dihydrotestosterone / Q000097:blood; D004311:Double-Blind Method; D000068538:Dutasteride; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000473:pathology; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D011467:Prostate / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000097:blood
D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D018952:Antigens, CD34; D001378:Azasteroids; D013196:Dihydrotestosterone; D013739:Testosterone; D000068538:Dutasteride