GROWTH-INHIBITION OF ANDROGEN-INSENSITIVE HUMAN PROSTATE CARCINOMA-CELLS BY A 19-NORSTEROID DERIVATIVE AGENT, MIFEPRISTONE

Mifepristone, also known as RU 486, is a 19-norsteroid derivative. Cur rently, mifepristone is being tested in clinical trials on meningioma and breast cancer. In this study we analyzed whether mifepristone coul d inhibit the growth of human prostate cancer cells including androgen -insensitive (PC-3 and DU145) and androgen-sensitive (LNCaP) cell line s. At 1-nM concentration, mifepristone exhibited a marginal stimulator y action on LNCaP and PC-3 cells. Nevertheless, a dose-dependent growt h inhibition on those same cell lines was observed at concentrations o f 1 mu M and 10 mu M Twenty-day exposure to the clinically achievable concentration of 1 mu M mifepristone resulted in consistent inhibition of all three cell lines studied. Furthermore, this in vitro growth in hibition was reflected in an in vivo nude mouse system. Mifepristone a t the dosage of 4 mg/100 g body weight completely suppressed the growt h of PC-3 tumors for 21 days, although this was followed by a growth r ate similar to that of the control tumor. To understand the possible m echanism of mifepristone inhibition, PC-3 cells were exposed to mifepr istone in comparison with dexamethasone (Dex), progesterone, and 5 alp ha-dihydrotestosterone (DHT), each at 1-mu M concentration. The result s demonstrated that while both DHT and Dex alone had essentially no ef fect on cell growth, progesterone alone resulted in a 20% growth inhib ition, while mifepristone had more than 60% inhibition with a 16-day e xposure. At an equal concentration, the degree of growth inhibition of PC-3 cells by mifepristone or progesterone was partially diminished b y simultaneous exposure to Dex. In conclusion, our results demonstrate d that the growth of androgen-insensitive prostate cancer cells can be directly inhibited by mifepristone in cultures. This in vitro inhibit ion is reflected in xenografted tumors. (C) 1995 Wiley-Liss, Inc.