The Effect of Cyclooxygenase-2 Inhibitor on the Gene Expression Profile of N-butyl-N-(4-hydroxybutyl) nitrosamine-induced Rat Urinary Bladder Cancer / 대한비뇨기과학회지

PURPOSE: Cyclooxygenase (COX)-2 plays an important role in promoting cancer cell proliferation and angiogenesis in human bladder cancer. In this study, we investigated the antitumor or antiangiogenic effects of selective COX-2 inhibitor on N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder tumorigenesis. MATERIALS AND METHODS: Forty male Fischer 344 rats (control) were given only 0.05% BBN, while 40 rats (experimental) were administered 1,500mg/ kg celecoxib once daily and this treatment started from 1 week before their BBN treatment. Ten rats from the control groups and the experimental groups were then sacrificed at 4, 12, 16 and 24 weeks after BBN treatment. We observed all the bladders macroscopically as well as microscopically, and we measured the COX-2 expression in the bladder tissues. Utilizing a cDNA microarray, we analyzed the significant differences of gene expression between the 12 week-control group and the 12 week-experimental group. RESULTS: The incidence of tumor was lower in the experimental group than in the control group from week 12 to week 24. The COX-2 expressions were more significantly decreased via the BBN induction (p<0.05) in the experimental groups than in the control groups after 4 weeks. For the 12 week-experimental group, there were 15 genes altered by the administration of selective COX-2 inhibitor, and the selective COX-2 inhibitor especially regulated transgelin, membrane metallo endopeptidase and apolipoprotein E of these 15 genes to prevent the incidence of bladder tumor. CONCLUSIONS: Selective COX-2 inhibitor has an inhibitory effect on BBN-induced rat bladder tumorigenesis. In the pre-neoplastic phase, selective COX-2 inhibitor regulates transgelin, membrane metallo endopeptidase and apolipoprotein E to prevent the incidence of bladder tumor.

Cyclooxygenase-2 Inhibitor Delayed the Tumorigenesis of N-Butyl-N-(4-hydroxybutyl)nitrosamine-induced Rat Urinary Bladder Cancer Model / 대한비뇨기과학회지

PURPOSE: Cyclooxygenase-2 (COX-2) plays an important role in promoting cancer cell proliferation and angiogenesis in human bladder cancer. The selective COX-2 inhibitor has antitumor activities in vivo and in vitro in a variety of tumor types. In this study, the antitumor or antiangiogenic effects of selective COX-2 inhibitor on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder tumorigenesis were investigated. MATERIALS AND METHODS: Forty male Fischer 344 rats (Control group) were given only 0.05% BBN in water ad libitum, while 40 others (Experimental group) were administered 1,500mug/kg celecoxib once daily through the gavage tube, which started 1 week before the BBN treatment. Ten rats were used as the normal bladder. Ten rats from the control and experimental group were sacrificed 4, 12, 16, and 24 weeks after the start of the BBN treatment. All bladders were evaluated both macroscopically and microscopically. We also measured COX-2 expression, microvessel density (MVD), and vascular endothelial growth factor (VEGF) protein concentrations in the bladder tissues. RESULTS: Macroscopically and microscopically, the incidence of tumor was lower in the experimental group than in the control group from the 12th week to the 24th week. Each incidence of tumor in week 12, week 16, and week 24 was 20%, 50%, and 80% in the control group and 0%, 20%, and 40% in the experimental group, respectively. In both the control and experimental groups, COX-2 expression had a tendency to be concentrated in the cytoplasm of the epithelial cells of the papillary tumor and the endothelial cells adjacent to the vessel the basal layer of bladder. COX-2 and VEGF expression were significantly more decreased in the experimental groups than in the control groups after 4 weeks from the BBN induction (p<0.05). MVD was significantly decreased in the experimental group at week 16 (p<0.05). CONCLUSIONS: The selective COX-2 inhibitor has an inhibitory effect on BBN-induced rat bladder tumorigenesis because of its partially antiangiogenic properties. In the future, the selective COX-2 inhibitor could be expected to play an important role as a chemo-preventive agent and as therapeutic aids in bladder cancer if these inhibitory effects can be reproduced in human bladder tumorigenesis.