The chemopreventive efficacies of
raloxifene and
nimesulide, an anti-
estrogen but with anti-
androgen action and a
cyclooxygenase-2 (COX-2) selective inhibitor, respectively, were evaluated in
probasin/SV40
T antigen (Tag) transgenic (TG) rats. The treatment groups were placebo,
nimesulide (400 p.p.m. in basal diet p.o.),
raloxifene (slow-release pellets implanted s.c., 5 mg/kg/day),
raloxifene (5 mg/kg/day) plus
nimesulide (400 p.p.m.), and
raloxifene (10 mg/kg/day) plus
nimesulide (400 p.p.m.). Animals were killed
at 17 weeks of age, and prostate tissues were harvested and weighed by lobes. Tissues were evaluated by histology, immunohistochemistry, and western blot analyses and blood was collected to measure the
testosterone levels. All the animals in the placebo group had
tumors in each lobe compared with only 43% each in the dorsolateral (DLP) and anterior prostate (AP) of the animals treated with
raloxifene (10 mg/kg/day) plus
nimesulide. The total prostate weights and
adenocarcinoma portions were significantly reduced in the three
raloxifene-treated groups, whereas atrophic glands were increased. There were no significant differences between the
nimesulide alone and placebo groups or between the
raloxifene (5 mg/kg/day) alone and
raloxifene (5 mg/kg/day) plus
nimesulide group, suggesting a lack of
cancer preventive effects of the
COX-2 inhibitor in this animal model.
PCNA positive rates in ventral prostate (VP) and DLP, and
androgen receptor (AR) levels in VP were significantly reduced in the three
raloxifene-treated groups. Furthermore, circulating
testosterone was decreased after
raloxifene (10 mg/kg/day) plus
nimesulide treatment. These results demonstrate that
raloxifene, but not
nimesulide, inhibits prostate
carcinogenesis in SV40 Tag TG rats associated with a decline in circulating
testosterone levels and a loss of AR expression, as well as an inhibition of cell proliferation.