Antitumor activity of mifepristone in the human LNCaP, LNCaP-C4, and LNCaP-C4-2 prostate cancer models in nude mice

BACKGROUND. Antiprogestins are a promising new class of mammary tumor inhib itors with a unique mechanism of action. Previously published results also suggest a tumor-inhibitory effect of antiprogestins in prostate cancer mode ls. The objective of the present studies was to determine whether androgen- sensitive and androgen-insensitive Variants of the well-characterized LNCaP human prostate cancer cell line exhibit stable differences in their sensit ivity to in vivo antitumor activity of the antiprogestin, mifepristone. METHODS. Exponentially growing LNCaP, LNCaP-C4, and LNCaP-C4-2 prostate can cer cells in culture were mixed with Matrigel and injected subcutaneously ( s.c.) into the flank of 6-8-week-old male nude mice. The tumors were permit ted to grow until they reached a volume of 270-300 mm(3). The animals were then randomly assigned to two groups. One group received mifepristone (50 m g/kg/day s.c.). Control animals were treated with vehicle. Tumor volume was determined every 4 days. After 28 days of treatment, the tumors were harve sted and wet weights were determined. RESULTS. The inoculated tumor cells produced progressively growing tumors i n male nude mice. However, the androgen-insensitive LNCaP-C4-2 cells showed the most aggressive and most rapid growth rate and shortest time to tumor progression. The tumors derived from the LNCaP-C4 cells exhibited a higher rate of tumor growth as compared with those derived from the parental andro gen-sensitive LNCaP cells. In all three models, mifepristone treatment caus ed a significant retardation of tumor progression: after 28 days of treatme nt, about 50% inhibition of tumor weight was observed in the mifepristone t reatment groups (P < 0.05) compared with the corresponding control groups. CONCLUSIONS. This is the first report demonstrating significant antitumor a ctivity of mifepristone in both androgen-sensitive and androgen-insensitive variants of the LNCaP human prostate cancer model in nude mice. These resu lts suggest a potential clinical benefit of the use of antiprogestins as a novel nonandrogen ablation therapeutic approach in the management of prosta te cancer. (C) 2000 Wiley-Liss,Inc.