Korean J Urol.  2004 Jun;45(6):578-584.

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

• Kwon SM
• Oh HY
• Kim SI
• Hong SJ

Abstract

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.

Keyword

Butylhydroxybutylnitrosamine; Bladder cancer; Angiogenic factor; VEGF; Factor VIII-related antigen

MeSH Terms

Angiogenesis Inducing Agents
Animals
Butylhydroxybutylnitrosamine
Carcinogenesis*
Cell Proliferation
Cyclooxygenase 2*
Cytoplasm
Endothelial Cells
Epithelial Cells
Humans
Incidence
Male
Microvessels
Rats*
Urinary Bladder Neoplasms*
Urinary Bladder*
Vascular Endothelial Growth Factor A
von Willebrand Factor
Water
Celecoxib
Angiogenesis Inducing Agents
Butylhydroxybutylnitrosamine
Cyclooxygenase 2
Vascular Endothelial Growth Factor A
Water
von Willebrand Factor