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Sequential androgen blockade: a biological study in the inhibition of prostatic growth
1Department of Surgery, University of Toronto, Ontario, Canada.
Abstract:
We attempted to determine the effects of the combination of a 5-alpha reductase inhibitor and an antiandrogen on rat ventral prostate and seminal vesicle weight. We also attempted to determine whether the prostatic cell death gene TRPM-2 would be expressed using this combination of drugs. Adult male Sprague-Dawley rats were randomly assigned to 7 groups of 15 animals. Four groups served as controls: an intact group sacrificed at the initiation of the trial (group 1), a castrate control group (group 2), an intact control group (group 3), and a group treated with the combination of an LHRH agonist plus antiandrogen (group 7). Three other groups were treated with daily subcutaneous injections of 5 alpha reductase inhibitor (group 5), a nonsteroidal pure antiandrogen (group 4) or both (group 6). After 5 days of treatment 5 animals in each group were sacrificed and prostatic tissue was assayed for the androgen repressed prostatic cell death gene TRPM-2. At 30 days (35 days for group 7) the remaining animals were sacrificed and their ventral prostates, seminal vesicles, and testes (except group 3) were weighed. The combination group (group 6) had a significantly lower prostate weight than either of the monotherapy groups (4, 5), or intact control groups, was equivalent to group 7 but was significantly heavier than the castrate group 2. The seminal vesicle weights of the combination group 6 were significantly lower than the monotherapy groups (4, 5), intact control group, castrate group (3) and was equivalent to group 7. Only castration was able to induce expression of the cell death gene TRPM-2. In this model, the combination of 5 alpha reductase inhibitor and an antiandrogen is as effective a mode of androgen ablation as combination therapy of LHRH agonist plus antiandrogen. Clinically, this combination may translate into adequate androgen blockade without impotence or other side effects of testosterone deprivation. Clinical trials appear warranted to assess this hypothesis.
Insights
Combining a 5-alpha reductase inhibitor and an antiandrogen effectively reduces prostate and seminal vesicle size in rats, similar to other androgen ablation methods. This combination may offer androgen blockade without side effects like impotence.
Area of Science:
- Endocrinology
- Urology
- Molecular Biology
Background:
- Androgen deprivation therapy is crucial for managing prostate cancer.
- Current therapies can cause significant side effects, including impotence.
- Novel therapeutic combinations are needed to optimize androgen blockade.
Purpose of the Study:
- To evaluate the efficacy of a combined 5-alpha reductase inhibitor and antiandrogen therapy.
- To assess the impact of this combination on rat ventral prostate and seminal vesicle weights.
- To investigate the expression of the TRPM-2 cell death gene under this treatment regimen.
Main Methods:
- Adult male Sprague-Dawley rats were assigned to seven groups, including controls and treatment arms.
- Treatments involved daily subcutaneous injections of a 5-alpha reductase inhibitor, an antiandrogen, or both.
- Prostate tissue was analyzed for TRPM-2 gene expression, and organ weights were recorded after 30-35 days.
Main Results:
- The combination therapy significantly reduced prostate and seminal vesicle weights compared to monotherapy.
- The combination's efficacy in reducing organ weight was comparable to LHRH agonist plus antiandrogen therapy.
- Only castration induced the expression of the TRPM-2 cell death gene; the combination therapy did not.
Conclusions:
- The combination of a 5-alpha reductase inhibitor and an antiandrogen provides effective androgen ablation in this rat model.
- This therapeutic approach may achieve adequate androgen blockade with potentially fewer side effects than current methods.
- Clinical trials are warranted to explore the potential benefits of this combination therapy in patients.