Carcinogenesis Advance Access published online on February 24, 2005
Carcinogenesis, doi:10.1093/carcin/bgi056
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1 Onco-Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
* To whom correspondence should be addressed. The chemopreventive efficacies of raloxifene and nimesulide, an antiestrogen but with anti-androgen action and a COX-2 selective inhibitor, respectively, were evaluated in probasin/ SV40 T antigen (Tag) transgenic (TG) rats. The treatment groups were placebo, nimesulide (400 ppm in basal diet p.o.), raloxifene (slow-release pellets implanted s.c., 5 mg/kg/day), raloxifene (5 mg/kg/day) plus nimesulide (400 ppm), and raloxifene (10 mg/kg/day) plus nimesulide (400 ppm). Animals were sacrificed 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 testosterone levels. All 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 nimesulide alone and placebo groups or between raloxifene (5 mg/kg/day) alone and raloxifene (5 mg/kg/day) plus nimesulide, 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 three raloxifene-treated group. 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 declined circulating testosterone and a loss of AR expression, as well as an inhibition of cell proliferation.
Received November 12, 2004
Revised February 1, 2005
Accepted February 16, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by raloxifene, an antiestrogen with anti-androgen action, but not nimesulide, a selective cyclooxygenase-2 inhibitor
2 Onco-Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
3 The Second Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
4 Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
Katsumi Imaida, E-mail: imaida{at}med.kagawa-u.ac.jp
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