Preventive and therapeutic efficacy of finasteride and dutasteride in TRAMP mice

Background: The prostate cancer prevention trial (PCPT) and Reduction by dutasteride of Prostate Cancer Events (REDUCE) trial found that 5α-reductase (5αR) inhibitors finasteride and dutasteride respectively, decreased prostate cancer prevalence but also increased the incidence of high-grade tumors. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have high 5αR1 and low 5αR2 expression. Because finasteride inhibits only 5αR2, we hypothesized that it would not be as efficacious in preventing prostate cancer development and/or progression in C57BL/6 TRAMP x FVB mice as dutasteride, which inhibits both 5αR1 and 5αR2. Method/Principal Findings: Six-week-old C57BL/6 TRAMP x FVB male mice were randomized to AIN93G control or pre- and post- finasteride and dutasteride diet (83.3 mg drug/kg diet) groups (n =30–33) that began at 6 and 12 weeks of age, respectively, and were terminated at 20 weeks of age. The pre- and post- finasteride and dutasteride groups were designed to test the preventive and therapeutic efficacy of the drugs, respectively. Final body weights, genitourinary tract weights, and genitourinary tract weights as percentage of body weights were significantly decreased in the Pre- and Post-dutasteride groups compared with the control. The Post-dutasteride group showed the greatest inhibition of prostatic intraepithelial neoplasia progression and prostate cancer development. Surprisingly, the Post-dutasteride group showed improved outcomes compared with the Pre-dutasteride group, which had increased incidence of high-grade carcinoma as the most common and most severe lesions in a majority of prostate lobes. Consistent with our hypothesis, we found little benefit from the finasteride diets, and they increased the incidence of high-grade carcinoma. Conclusion: Our findings have commonalities with previously reported PCPT, REDUCE, and the Reduction by dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial results. Our results may support the therapeutic use of dutasteride, but not finasteride, for therapeutic or preventive use

The effect of finasteride and dutasteride on the growth of WPE1-NA22 prostate cancer xenografts in nude mice

Background: 5 alpha-reductase 1 (5alphaR1) and 5alpha-reductase 2 (5alphaR2) convert testosterone into the more potent androgen dihydrotestosterone. 5alphaR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have increased 5alphaR1 and decreased 5alphaR2 expression. Previously, finasteride (5alphaR2 inhibitor) treatment begun 3 weeks post-tumor implantation had no effect on Dunning R3327-H rat prostate tumor growth. We believe the tumor compensated for finasteride treatment by increasing tumor 5alphaR1 expression or activity. We hypothesize that finasteride treatment would not significantly alter tumor growth even if begun before tumor implantation, whereas dutasteride (5alphaR1 and 5alphaR2 inhibitor) treatment would decrease tumor growth regardless of whether treatment was initiated before or after tumor implantation. Methodology/Principal Findings: Sixty 8-week-old male nude mice were randomized to Control, Pre- and Post-Finasteride, and Pre- and Post-Dutasteride (83.3 mg drug/kg diet) diet groups. Pre- and post-groups began their treatment diets 1–2 weeks prior to or 3 weeks after subcutaneous injection of 1x10[5th power] WPE1-NA22 human prostate cancer cells, respectively. Tumors were allowed to grow for 22 weeks; tumor areas, body weights, and food intakes were measured weekly. At study’s conclusion, prostate and seminal vesicle weights were significantly decreased in all treatment groups versus the control; dutasteride intake significantly decreased seminal vesicle weights compared to finasteride intake. No differences were measured in final tumor areas or tumor weights between groups, likely due to poor tumor growth. In follow-up studies, proliferation of WPE1-NA22 prostate cancer cells and parent line RWPE-1 prostate epithelial cells were unaltered by treatment with testosterone, dihydrotestosterone, or mibolerone, suggesting that these cell lines are not androgensensitive. Conclusion: The lack of response of WPE1-NA22 prostate cancer cells to androgen treatment may explain the inadequate tumor growth observed. Additional studies are needed to determine whether finasteride and dutasteride are effective in decreasing prostate cancer development/growth

Tumor area (n = 20–24) of tumor sites.

<p>Zeros were recorded for tumor sites without tumors; no significant differences between groups.</p

Tumor incidence (n = 20–24) in tumor sites.

<p>Zeros were recorded for tumor sites without a tumor; no significant differences between groups.</p

RPWE-1 (10,000 cells/well) cell viability was not altered by daily treatment of testosterone (0.1 nM–30 nM), dihydrotestosterone (0.03 nM–100 nM), or mibolerone (0.01 nM–20 nM) after a 5-day treatment period; no significant treatment effects.

<p>RPWE-1 (10,000 cells/well) cell viability was not altered by daily treatment of testosterone (0.1 nM–30 nM), dihydrotestosterone (0.03 nM–100 nM), or mibolerone (0.01 nM–20 nM) after a 5-day treatment period; no significant treatment effects.</p

Animal study design: After receipt, mice were acclimated for 1 week then randomized into Control, Pre-Finasteride, Post-Finasteride, Pre-Dutasteride, and Post-Dutasteride groups (n = 12).

<p>Pre- and post-groups began their treatment diets 1–2 weeks prior or 3 weeks after WPE1-NA22 cell injection, respectively. The study was terminated 22 weeks post-tumor implantation.</p