Effects of dutasteride on prostate carcinoma primary cultures: a comparative study with finasteride and MK386.
OBJECTIVE
The profound decrease in serum dihydrotestosterone observed with the dual 5alpha-reductase inhibitor dutasteride makes it an attractive agent for prostate cancer therapy. To our knowledge we compared for the first time the antitumor effect of dutasteride with that of the specific 5alpha-reductase-1 inhibitor MK386 and the specific 5alpha-reductase-2 inhibitor finasteride in human prostate primary cultures.


METHODS
Biochemical markers of the cellular response to 5alpha-reductase inhibitors were evaluated in primary cultures of prostate epithelial cancer cells from 54 patients with prostate carcinoma.


RESULTS
In our cohort of 54 patients prostate cancer cell growth decreased with dutasteride in 42 (about 78%), whereas in 21 (39%) it decreased with finasteride or MK386 alone. We observed a relationship between the levels of 5alpha-reductase enzymes in cell culture extracts and those revealed by immunohistochemistry in sections of samples from which we established primary cultures. Finasteride effects depended on 5alpha-reductase-2 levels and they were higher when the 5alpha-reductase-1:2 ratio was low. However, dutasteride effects were related to 5alpha-reductase-1 and 2 levels, and were not influenced by the 5alpha-reductase-1:2 ratio. Conversely the effects of MK386 were related to 5alpha-reductase-1 levels and they were higher when the 5alpha-reductase-1:2 ratio was high.


CONCLUSIONS
Our data may provide a rationale for the use of a dual 5alpha-reductase inhibitor rather than a mono specific inhibitor for the prevention or treatment of early prostate cancer. This finding appears to confirm some preliminary clinical results and it could be due to the simultaneous presence of each 5alpha-reductase isoenzyme in prostate tumor cells.
Festuccia
Claudio
C
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Gravina
Giovanni Luca
GL
Muzi
Paola
P
Pomante
Roberto
R
Angelucci
Adriano
A
Vicentini
Carlo
C
Bologna
Mauro
M
D058891:5-alpha Reductase Inhibitors; D000368:Aged; D001378:Azasteroids / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D000068538:Dutasteride; D018120:Finasteride / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
C090665:4,7beta-dimethyl-4-azacholestan-3-one; D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D018120:Finasteride; D000068538:Dutasteride