The carcinogenicity of low dietary levels of the antioxidants butylated hydroxyanisole (BHA), caffeic acid, sesamol, 4-methoxyphenol (4-MP) and catechol, known to target the forestomach or glandular stomach, were examined alone or in combination in a 2-year long-term experiment and their modifying effects assessed in a medium-term multiorgan model. In the carcinogenicity study, groups of 30-31 male F344 rats were treated with 0.4% BHA, 0.4% caffeic acid, 0.4% sesamol, 0.4% 4-MP and 0.16% catechol either alone or in combination for up to 104 weeks and then killed. In the medium-term multi-organ model, groups of 10 to 15 male F344 rats were given diethylnitrosamine (DEN), N-methylnitrosourea (MNU), 1,2-dimethylhydrazine (DMH), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) for a total multiple initiation period of 4 weeks (DMBDD treatment). BHA, caffeic acid, sesamol and 4-MP, each at doses of 0.4% or 0.08%, and catechol at doses of 0.16% or 0.032% were administered in the diet either alone or in combination after completion of the initiation regimen. All surviving animals were killed at the end of week 28, and major organs were examined histopathologically. In the carcinogenicity study, slightly increased incidences of forestomach papillomas were found in the sesamol- (15.8%), caffeic acid- (14.8%), catechol- (3%) and 4-MP- (11.5%) treated groups as compared with basal diet (0%), and a significant increase was observed with the five antioxidants in combination (42.9%, P < 0.001). In a medium-term multiorgan carcinogenesis model, incidences of forestomach papillomas and/or carcinomas were increased in each high dose group, but additive or synergistic effects were not found in the combination group. In the low dose case, the incidence of forestomach papillomas was significantly increased only in the combination group. With regard to other organs, the incidence of colon tumors was significantly decreased only in the high dose combination group. The results indicate that even at low dose levels phenolic compounds can exert additive/synergistic effect on carcinogenesis.

No abstract

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.