When the human
prostate cancer cell line, LNCaP 104-S, the growth of which is stimulated by physiological levels of
androgen, is cultured in
androgen-depleted medium for > 100 passages, the cells, now called LNCaP 104-R2, are proliferatively repressed by low concentrations of
androgens. LNCaP 104-R2 cells formed
tumors in castrated male athymic nude mice.
Testosterone propionate (TP) treatment prevented LNCaP 104-R2
tumor growth and caused regression of established
tumors in these mice. Such a
tumor-suppressive effect was not observed with
tumors derived from LNCaP 104-S cells or
androgen receptor-negative human
prostate cancer PC-3 cells.
5 alpha-Dihydrotestosterone, but not
5 beta-dihydrotestosterone,
17 beta-estradiol, or
medroxyprogesterone acetate, also inhibited LNCaP 104-R2
tumor growth. Removal of TP or implantation of
finasteride, a
5 alpha-reductase inhibitor, in nude mice bearing TP implants resulted in the regrowth of LNCaP 104-R2
tumors. Within 1 week after TP implantation, LNCaP 104-R2
tumors exhibited massive
necrosis with severe
hemorrhage. Three weeks later, these
tumors showed
fibrosis with infiltration of chronic inflammatory cells and scattered
carcinoma cells exhibiting degeneration. TP treatment of mice with LNCaP 104-R2
tumors reduced
tumor androgen receptor and c-myc
mRNA levels but increased
prostate-specific antigen in serum- and
prostate-specific antigen mRNA in
tumors. Although
androgen ablation has been the standard treatment for metastatic
prostate cancer for > 50 years, our study shows that
androgen supplementation
therapy may be beneficial for treatment of certain types of human
prostate cancer and that the use of
5 alpha-reductase inhibitors, such as
finasteride or anti-
androgens, in the general treatment of metastatic
prostate cancer may require careful assessment.