Inhibition of rat prostate carcinogenesis by a 5alpha-reductase inhibitor, FK143.
BACKGROUND
Androgen levels in the prostate may influence carcinogenesis in this organ. Inhibitors of the enzyme 5alpha-reductase block conversion of testosterone to the more active androgen dihydrotestosterone. The use of a 5alpha-reductase inhibitor, finasteride, in the chemoprevention of prostate cancer is being evaluated in a clinical trial.


OBJECTIVE
This study was conducted to determine if a 5alpha-reductase inhibitor, FK143, inhibits the development of prostate cancer in rats.


METHODS
Male ACI/Seg rats, which spontaneously develop prostate cancer, were randomly assigned at 80 weeks of age to receive one of three diets (n = 35/group) containing 0 (i.e., control group), 20, or 200 ppm FK143. At 140 weeks of age, the animals were killed, and the prostates were removed and examined for histopathologic features in addition to being assayed for androgen concentrations. Two-sided statistical tests were used to calculate all P values.


RESULTS
The incidence of prostate carcinoma in the control group was 62.9% (22 of 35 rats); in the group fed the 20 ppm FK143-containing diet, it was 45.7% (16 of 35); and in the group fed the 200 ppm FK143-containing diet, it was 67.6% (23 of 34) (overall, P = .153). The corresponding incidences of macroscopic lesions were 17.1% (six of 35 rats), 0% (none of 35), and 23.5% (eight of 34), respectively (overall, P = .004). The incidence of macroscopic lesions in the prostates of rats in the 20-ppm diet group was significantly lower than that in the control group (P = .029) or that in the 200-ppm diet group (P = .003). Intraprostatic dihydrotestosterone content was significantly lower in rats in the groups fed diets containing 20 or 200 ppm FK143 (mean values: 4.51 and 4.33 pg/mg wet weight of prostate tissue, respectively) than in the control group (6.10 pg/mg) (overall, P<.001); by contrast, testosterone was higher in the 200-ppm diet group (2.09 pg/mg) than in the control group (1.08 pg/mg) or the 20-ppm diet group (1.21 pg/mg) (overall, P<.001).


CONCLUSIONS
FK143, when fed to rats at 20 or 200 ppm, significantly reduced the level of dihydrotestosterone in their prostate tissue. However, the incidence of macroscopic cancer in the prostate was suppressed in rats consuming the 20 ppm FK143-containing diet but not in those consuming the 200-ppm diet. The lack of dose dependence for the chemopreventive activity of FK143 may be explained by the reciprocal increase of tissue testosterone in the 200-ppm diet group.


CONCLUSIONS
The 5alpha-reductase inhibitor FK143 may, at specific doses, reduce the incidence of spontaneously developing prostate cancer; however, whether these findings in rats will apply to humans remains to be determined.
Homma
Y
Y
Department of Urology, Faculty of Medicine, The University of Tokyo, Japan.
Kaneko
M
M
Kondo
Y
Y
Kawabe
K
K
Kakizoe
T
T
D058891:5-alpha Reductase Inhibitors; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D010654:Phenylbutyrates / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000517:prevention & control*; D051381:Rats; D011912:Rats, Inbred ACI
C093354:4-(3-(3-(bis(4-isobutylphenyl)methylamino)benzoyl)-1H-indol-1-yl)butyric acid; D058891:5-alpha Reductase Inhibitors; D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D010654:Phenylbutyrates