Chemopreventive potential of fumaric acid, N-acetylcysteine, N-(4-hydroxyphenyl) retinamide and β-carotene for tobacco-nitrosamine-induced lung tumors in A/J mice1

Abstract Four agents, fumaric acid (FA), N- acetylcysteine ( N AC), N -(4-hydroxyphenyl) retinamide (4-HPR) and β -carotene ( β -CT), were evaluated for potential chemopreventive activity using the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor model in female A/J mice. The agents were evaluated in both 16-week and 52-week bioassays at two dose levels corresponding to 0.8 maximum tolerated dose (MTD) and 0.4 MTD administered throughout the bioassay either in the diet (FA, 160 and 80 mmol/kg diet; N AC, 160 and 80 mmol/kg diet; 4-HPR, 4 and 2 mmol/kg diet) or by subcutaneous injection twice a week ( β -CT, 32 and 16 mg/kg b.w.). Mice were treated with a single i.p. dose of 10 μ mol NNK in saline 1 week after administration of test agent. Lung adenomas were evaluated in the 16-week bioassay, whereas both adenomas and adenocarcinomas of the lung were determined in the 52-week bioassay. Both bioassays showed that all four agents did not significantly inhibit the total tumor incidence and multiplicity of the lung. However, the incidence of adenocarcinomas was reduced ( P N AC or 0.8 MTD β -CT compared with the NNK control group. The decreases in adenocarcinomas were accompanied by corresponding increases in adenomas in these treatment groups. Thus, this study showed that FA, N AC, 4-HPR and β -CT did not inhibit the total tumor formation, however, at the higher doses both N AC and β -CT significantly retarded the malignant progression in the lung of NNK-treated A/J mice.