Sequential androgen blockade: a biological study in the inhibition of prostatic growth.
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.
Fleshner
N E
NE
Department of Surgery, University of Toronto, Ontario, Canada.
Trachtenberg
J
J
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D002064:Buserelin / Q000494:pharmacology*; D051152:Clusterin; D018120:Finasteride; D005485:Flutamide / Q000494:pharmacology*; D006023:Glycoproteins / Q000096:biosynthesis*; D008297:Male; D018832:Molecular Chaperones; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000254:growth & development*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012669:Seminal Vesicles / Q000187:drug effects* / Q000254:growth & development*
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D001378:Azasteroids; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D018120:Finasteride; D005485:Flutamide; D002064:Buserelin