Consideration of the use of 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5- alpha-androstan-3-one (4MA), a 5 alpha-reductase inhibitor, in prostate cancer therapy.
We investigated the effect of 17 beta-N,N-diethylcarbamoyl-4-methyl-4aza- 5 alpha-androstan-3-one (4MA), a 5 alpha-reductase inhibitor, on growth inhibition of androgen-sensitive rat prostatic tumour (R3327-H) and correlated it with changes in weight of normal androgen target tissues and with levels of androgens. Groups of male Copenhagen rats were treated for 28 days with a daily injection of various, increasing doses of 4MA (0.01-4.0 mg/day) and the results were compared with control (vehicle-treated) and with castrated animals. 4MA decreased tumour growth rate in a dose-dependent manner, which was reflected in a decreased incorporation of BrdUrd in DNA of glandular epithelial cells in the tumour. Normal prostate wet weight was also decreased after high-dose 4MA treatment while serum testosterone levels were not affected by 4MA treatment. Contrary to expectations, however, tissue levels of dihydrotestosterone in tumour and ventral prostate were still considerable in 4MA-treated animals. The tumour-inhibiting action of 4MA, therefore, has to be interpreted as not being purely due to 5 alpha-reductase inhibition. On the other hand, it was not possible to demonstrate any direct tumoricidal effect of 4MA in vitro. The relevance of these findings in terms of the endocrine mechanism of action of 4MA on tumour growth is discussed.
Geldof
A A
AA
Department of Endocrinology, Acad. Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands.
Meulenbroek
M F
MF
Dijkstra
I
I
Bohlken
S
S
Rao
B R
BR
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000097:blood / Q000378:metabolism; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D008297:Male; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000033:anatomy & histology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013256:Steroids / Q000097:blood
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D000728:Androgens; D001378:Azasteroids; D013256:Steroids; D013196:Dihydrotestosterone; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one