RESPONSES OF LNCAP PROSTATIC ADENOCARCINOMA CELL-CULTURES TO LY300502, A BENZOQUINOLINONE HUMAN TYPE-I 5-ALPHA-REDUCTASE INHIBITOR

We evaluated the metabolic inhibitory, antiproliferative, and antisecr etory effects of LY300502, a benzoquinolinone human-specific type I-se lective steroid 5 alpha-reductase inhibitor in LNCaP human prostatic a denocarcinoma cell cultures. Reductive metabolism of [H-3-T] in the LN CaP cells was inhibited in a concentration-dependent manner by LY30050 2 (IC50 similar or equal to 5.77 nM). The proliferative responses of L NCaP cells to LY300502 were examined in the presence of 0.1 nM testost erone (T), a concentration that stimulates maximal LNCaP cellular prol iferation. Addition of 0.1 nM T to the culture media significantly sti mulated LNCaP cell numbers 40% above control levels. LY300502 signific antly antagonized T-induced stimulation of LNCaP cellular proliferatio n at concentrations greater than 10 nM (P < 0.05), and at 1,000 nM com pletely blocked the mitogenic effects of T on LNCaP cells. In the abse nce of androgen, LY300502 had no effect on LNCaP cellular proliferatio n. In the presence of 100 nM T, an androgen concentration that maximal ly stimulates in vitro PSA production, LY300502 significantly antagoni zed T-induced PSA secretion at a concentration equal to or greater tha n 30 nM (P < 0.05). These studies provide the basis for additional inv estigations into the pathophysiologic significance of type I 5 alpha-r eductase to prostatic cancer and the potential utility of selective in hibitors as therapeutic agents. (C) 1996 Wiley-Liss, Inc.