The chemopreventive effects of
indomethacin (IM) on the enhancement of bladder
carcinogenesis and transitional-epithelial-cell proliferation by
butylated hydroxyanisole (
BHA) or
sodium L-ascorbate (Na-AsA) were investigated. All animals were given 0.05%
N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their
drinking water for 4 weeks. They then received 2%
BHA or 5% Na-AsA for 20 weeks, followed by 20 ppm IM in the
drinking water or normal tap water without supplement for a further 20 weeks, or
BHA or Na-AsA alone or concomitantly with IM for 40 weeks. No differences in
bladder-tumor development were found when IM was administered after cessation of
BHA or Na-AsA exposure. However, IM in combination with either
BHA or Na-AsA significantly reduced both the incidence and the multiplicity of
papillomas and
carcinomas as compared with the values of groups receiving
BHA or Na-AsA alone. This was associated with decreased
DNA synthesis and
prostaglandin (PG) E2 levels in the existing
bladder tumors. Combined treatment with IM did not exert any effects on
BHA forestomach
carcinogenesis. A separate 8-week combination study demonstrated that IM diminished the increase in expression of proliferation nuclear-cell
antigen (
PCNA) induced by
BHA or Na-AsA alone. The present results suggest that
PGE2 may be involved in promotion of rat bladder
carcinogenesis and that the PG synthesis blocker IM might exert preventive effects on the development of
bladder cancer in humans.