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 inhibitors with a unique mechanism of action. Previously published results also suggest a tumor-inhibitory effect of antiprogestins in prostate cancer models. 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 sensitivity to in vivo antitumor activity of the antiprogestin, mifepristone.


METHODS
Exponentially growing LNCaP, LNCaP-C4, and LNCaP-C4-2 prostate cancer 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 permitted 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 mg/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 harvested and wet weights were determined.


RESULTS
The inoculated tumor cells produced progressively growing tumors in 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 androgen-sensitive LNCaP cells. In all three models, mifepristone treatment caused a significant retardation of tumor progression: after 28 days of treatment, about 50% inhibition of tumor weight was observed in the mifepristone treatment groups (P < 0.05) compared with the corresponding control groups.


CONCLUSIONS
This is the first report demonstrating significant antitumor activity of mifepristone in both androgen-sensitive and androgen-insensitive variants of the LNCaP human prostate cancer model in nude mice. These results suggest a potential clinical benefit of the use of antiprogestins as a novel nonandrogen ablation therapeutic approach in the management of prostate cancer.
El Etreby
M F
MF
Section of Urology, Department of Surgery and Office of Biostatistics, Medical College of Georgia, Augusta, Georgia 30912-4050, USA.
Liang
Y
Y
Johnson
M H
MH
Lewis
R W
RW
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011897:Random Allocation; D014407:Tumor Cells, Cultured
D000728:Androgens; D006727:Hormone Antagonists; D015735:Mifepristone