Effects of androgen and antiandrogen treatment on canine prostatic arginine esterase.
A series of experiments were conducted to investigate the regulation of the primary secretory protein of the canine prostate, arginine esterase, by androgens and/or new antiandrogen under development. In the first experiment, castration decreased (P less than 0.05) prostatic arginine esterase levels relative to intact controls (0.26 +/- 0.1 and 17.0 +/- 0.1 mumole/min/mg protein, respectively). Treatment of castrate dogs with either 5, 10, or 20 silastic capsules (8 cm length) containing the androgen 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) plus 1 capsule containing estradiol-17 beta (E2) or the i.m. injection of 25 mg 3 alpha-diol and 0.25 mg E2 for 12 weeks resulted in a dose-dependent increase (P less than 0.05) in prostatic arginine esterase activity (6.8 +/- 1.7, 19.0 +/- 3.6, 21.3 +/- 0.9, and 14.2 +/- 0.7 mumole/min/mg protein, respectively). In the second experiment, steroid treatment (10 3 alpha-diol plus 1 E2 silastic capsules) of castrate dogs for 12 weeks resulted in prostatic arginine esterase activity of 17.8 +/- 2.3 mu mole/min/mg. Co-administration of the steroidal androgen receptor antagonist. Win 49,596 (WIN) at doses of 0.625, 2.5, 10, or 40 mg/kg/day p.o., dose-dependently inhibited (P less than 0.05) prostatic arginine esterase activity (14.9 +/- 1.1, 14.3 +/- 1.3, 3.4 +/- 1.9, and 0.21 +/- 0.1 mumole/min/mg, respectively) to levels similar to that observed in castrate controls (0.14 +/- 0.03 mumole/min/mg). Administration of the nonsteroidal androgen receptor antagonist flutamide at 10 mg/kg/day p.o. to steroid-induced dogs also inhibited (P less than 0.05) arginine esterase activity (0.07 +/- 0.02 mumole/min/mg). In the last experiment, treatment of intact dogs with WIN at 0.625, 2.5, 10, and 40 mg/kg/day for 16 weeks dose-dependently reduced (P less than 0.05) arginine esterase levels (17.0 +/- 1.0, 16.3 +/- 1.5, 10.2 +/- 1.2, and 3.9 +/- 2.5 mumole/min/mg, respectively) compared to intact controls (14.4 +/- 1.2 mumole/min/mg). Histomorphologic and ultrastructural evaluation of prostates from dogs indicated that antiandrogen treatment resulted in glandular epithelial atrophy as well as a reduction in the number of secretory granules. The results of these experiments support that canine prostatic arginine esterase activity is under androgenic control, can be inhibited by antiandrogen treatment and may serve as a functional marker of the androgenic state of the prostate. Whether the effects of androgen and antiandrogens on prostatic arginine esterase is direct or indirect due to a general inhibitory effect on secretory epithelial cell function requires additional study. Furthermore, subject to further evaluation, the steroidal androgen receptor antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)
Juniewicz
P E
PE
Department of Oncopharmacology, Sterling Research Group, Rensselaer, New York 12144.
Barbolt
T A
TA
Egy
M A
MA
Frenette
G
G
Dube
J Y
JY
Tremblay
R R
RR
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology*; D015113:Androstane-3,17-diol / Q000494:pharmacology; D000736:Androstenes / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology; D002214:Capsules; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D018120:Finasteride; D005485:Flutamide / Q000494:pharmacology; D006965:Hyperplasia / Q000188:drug therapy; D007273:Injections, Intramuscular; D008297:Male; D009570:Nitriles; D011278:Pregnanes / Q000494:pharmacology; D011467:Prostate / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D011468:Prostatectomy; D011720:Pyrazoles / Q000494:pharmacology; D014105:Tosyl Compounds
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D000728:Androgens; D000736:Androstenes; D000813:Anilides; D001378:Azasteroids; D002214:Capsules; D009570:Nitriles; D011278:Pregnanes; D011720:Pyrazoles; D014105:Tosyl Compounds; D015113:Androstane-3,17-diol; D004958:Estradiol; D018120:Finasteride; D005485:Flutamide; C053541:bicalutamide; C019724:arginine esterase; D002265:Carboxylic Ester Hydrolases; C060492:zanoterone