Effects of Dutasteride on Prostate Carcinoma Primary Cultures: A Comparative Study With Finasteride and MK386

Festuccia, Claudio; Gravina, Giovanni Luca; Muzi, Paola; Pomante, Roberto; Angelucci, Adriano; Vicentini, Carlo; Bologna, Mauro

doi:10.1016/j.juro.2008.02.036

« Previous Next »The Journal of Urology
Volume 180, Issue 1 , Pages 367-372, July 2008

Effects of Dutasteride on Prostate Carcinoma Primary Cultures: A Comparative Study With Finasteride and MK386

Claudio Festuccia
- Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
- Equal study contribution.
Giovanni Luca Gravina
- Department of Surgery, University of L'Aquila, L'Aquila, Italy
- Equal study contribution.
Paola Muzi
- Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
Roberto Pomante
- Pathology Department, G. Mazzini Hospital, Teramo, Italy
Adriano Angelucci
- Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
Carlo Vicentini
- Department of Surgery, University of L'Aquila, L'Aquila, Italy
Mauro Bologna
- Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
- Department of Basic and Applied Biology, University of L'Aquila, L'Aquila, Italy
- Correspondence: Department of Experimental Medicine, Via Vetoio, Coppito-2, 67100 L'Aquila, Italy (telephone: 39 0862 433527; FAX: 39 0862 433523).

Received 24 September 2007 published online 22 May 2008.

Purpose

The profound decrease in serum dihydrotestosterone observed with the dual 5α-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 5α-reductase-1 inhibitor MK386 and the specific 5α-reductase-2 inhibitor finasteride in human prostate primary cultures.

Materials and Methods

Biochemical markers of the cellular response to 5α-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 5α-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 5α-reductase-2 levels and they were higher when the 5α-reductase-1:2 ratio was low. However, dutasteride effects were related to 5α-reductase-1 and 2 levels, and were not influenced by the 5α-reductase-1:2 ratio. Conversely the effects of MK386 were related to 5α-reductase-1 levels and they were higher when the 5α-reductase-1:2 ratio was high.

Conclusions

Our data may provide a rationale for the use of a dual 5α-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 5α-reductase isoenzyme in prostate tumor cells.

Key Words: prostate, prostatic neoplasms, cholestenone 5 alpha-reductase, receptors, androgen, dutasteride

Abbreviations and Acronyms: AR, androgen receptor, DHT, dihydrotestosterone, IC₅₀, concentration inhibiting 50% response, IHC, immunohistochemistry, IR, immunoreactivity, SDR5A, steroid 5α-reductase, SRD5A1, type I SRD5A isoform, SRD5A2, type II SRD5A isoform