CHEMOPREVENTIVE POTENTIAL OF FUMARIC-ACID, N-ACETYLCYSTEINE, N-(4-HYDROXYPHENYL) RETINAMIDE AND BETA-CAROTENE FOR TOBACCO-NITROSAMINE-INDUCED LUNG-TUMORS IN A J MICE/

Four agents, fumaric acid (FA), N-acetylcysteine (NAG), N-(4-hydroxyph enyl) retinamide (4-HPR) and beta-carotene (beta-CT), were evaluated f or potential chemopreventive activity using the tobacco-specific carci nogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lun g 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 ma ximum tolerated dose (MTD) and 0.4 MTD administered throughout the bio assay either in the diet (FA, 160 and 80 mmol/kg diet; NAG, 160 and 80 mmol/kg diet; 4-HPR, 4 and 2 mmol/kg diet) or by subcutaneous injecti on twice a week (beta-CT, 32 and 16 mg/kg b.w.). Mice were treated wit h a single i.p. dose of 10 mu mol NNK in saline 1 week after administr ation of test agent. Lung adenomas were evaluated in the 16-week bioas say, whereas both adenomas and adenocarcinomas of the lung were determ ined in the 52-week bioassay. Both bioassays showed that all four agen ts did not significantly inhibit the total tumor incidence and multipl icity of the lung. However, the incidence of adenocarcinomas was reduc ed (P < 0.01) at 52 weeks in NNK groups given either 0.8 MTD NAC or 0. 8 MTD beta-CT compared with the NNK control group. The decreases in ad enocarcinomas were accompanied by corresponding increases in adenomas in these treatment groups. Thus, this study showed that FA, NAG, 4-HPR and beta-CT did not inhibit the total tumor formation, however, at th e higher doses both NAC and beta-CT significantly retarded the maligna nt progression in the lung of NNK-treated A/J mice. Published by Elsev ier Science Ireland Ltd.