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Effects of dutasteride on prostate carcinoma primary cultures: a comparative study with finasteride and MK386
Claudio Festuccia1, Giovanni Luca Gravina, Paola Muzi
1Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Purpose:
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.
Materials And 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.
Insights
Dutasteride, a dual 5alpha-reductase inhibitor, showed significant prostate cancer cell growth reduction. This dual action may be more effective than single inhibitors for early prostate cancer treatment.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- 5alpha-reductase inhibitors are investigated for prostate cancer therapy.
- Dutasteride, a dual inhibitor, profoundly decreases dihydrotestosterone.
- Specific inhibitors MK386 (5alpha-reductase-1) and finasteride (5alpha-reductase-2) also exist.
Purpose of the Study:
- To compare the antitumor effects of dutasteride, MK386, and finasteride.
- To evaluate these inhibitors in human prostate primary cancer cell cultures.
Main Methods:
- Primary prostate cancer cell cultures from 54 patients were used.
- Biochemical markers of cellular response to inhibitors were assessed.
- Enzyme levels and ratios (5alpha-reductase-1:2) were correlated with drug effects.
Main Results:
- Dutasteride decreased prostate cancer cell growth in 78% of patients.
- Finasteride or MK386 alone decreased growth in 39% of patients.
- Drug efficacy correlated with specific 5alpha-reductase isoenzyme levels and ratios.
Conclusions:
- Dual 5alpha-reductase inhibition with dutasteride may be superior to single inhibitors.
- This supports its use in early prostate cancer prevention or treatment.
- Simultaneous presence of both isoenzymes in tumors may explain dutasteride's efficacy.
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