A test of rats' tolerance for 3beta-acetoxyandrosta-1,5-dien-17-one ethylene ketal (ADEK), a new anti-androgen.
Following the demonstration that the androgen activity of androsta-5-ene-3beta,17beta-diol (Adiol) is not inhibited by the anti-androgens currently used to treat prostate cancer, we sought agents that would inhibit the androgenic function of Adiol as well as of dihydrotestosterone. The steroid 3beta-acetoxyandrosta-1,5-dien-17-one ethylene ketal (ADEK) met this criterion. Its tolerance was assessed in rats by oral and by subcutaneous administration for four weeks. Neither route of ADEK administration resulted in any behavioral changes. There was no effect on weight gain during the 28 days of steroid intake and no effect on the weight of the kidneys, heart, liver, testes, adrenals or the ventral lobe of the prostate glands. The seminal vesicles of the treated rats were 23-29% and the weights of the anterior prostates of the respective groups were 17-26% smaller than the controls. In contrast, the dorsolateral prostates were increased 26-55% as compared with the controls. There were no detectable changes in the histology of the kidneys, hearts, livers, testes and adrenals of any of the rats, but both groups of ADEK-treated rats had mild atrophic changes in their seminal vesicles and in the ventral lobe of their prostate glands. Both ADEK-treated groups showed focal glandular epithelial hyperplasia in the dorsolateral lobes in comparison with the control group. Orally administered ADEK was rapidly converted to several metabolites, which were nearly completely cleared from the blood within 4h.
Lardy
Henry
H
Department of Biochemistry, Institute for Enzyme Research, University of Wisconsin, Madison 53726, United States. halardy@wisc.edu
Marwah
Ashok
A
Zhong
Weixiong
W
Moore
Robert
R
Marwah
Padma
P
Thompson
Todd
T
Wilding
George
G
D000726:Androgen Antagonists / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D000730:Androstadienes / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D008297:Male; D015394:Molecular Structure; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
C474317:3-acetoxyandrost-1,5-dien-17-ethylene ketal; D000726:Androgen Antagonists; D000730:Androstadienes