Responses of LNCaP prostatic adenocarcinoma cell cultures to LY300502, a benzoquinolinone human type I 5alpha-reductase inhibitor.
We evaluate the metabolic inhibitory, antiproliferative, and antisecretory effects of LY300502, a benzoquinolinone human-specific type I-selective steroid 5alpha-reductase inhibitor in LNCaP human prostatic adenocarcinoma cell cultures. Reductive metabolism of [3H-T] in the LNCaP cells was inhibited in a concentration-dependent manner by LY300502 (IC50 approximately 5.77 nM). The proliferative responses of LNCaP cells to LY300502 were examined in the presence of 0.1 NM testosterone (T), a concentration that stimulates maximal LNCaP cell numbers 40% above control levels. LY300502 significantly anatagonized T-induced stimulation of LNCaP cellular proliferation at concentrations greater that 10 nM (P<0.05), and at 1,000 nMcompletely blocked the mitogenic effects of T on LNCaP cells. In the absence of androgen, LY300502 had no effect on LNCaP cellular proliferation. In the presence of 100 nM T, an androgen concentration that maximally stimulates in vitro PSA production, LY300502 significantly antagonized T-induced PSA secretion at a concentration equal to or greater than 30 nM (P<0.05). These studies provide the basis for additional investigations into the pathophysiologic significance of type I 5alpha-reductase to prostatic cancer and the potential utility of selective inhibitors as therapeutic agents.
Sutkowski
D M
DM
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
Audia
J E
JE
Goode
R L
RL
Hsiao
K C
KC
Leibovitch
I Y
IY
McNulty
A M
AM
Neubauer
B L
BL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015363:Quinolones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C098549:8-chloro-1,4,4a,5,6,10b-hexahydro-4-methylbenzo(f)quinolin-3(2H)-one; D004791:Enzyme Inhibitors; D015363:Quinolones; D013196:Dihydrotestosterone; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase; D017430:Prostate-Specific Antigen