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 (NAC), N-(4-hydroxyphenyl) retinamide (4-HPR) and beta-carotene (beta-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; NAC, 160 and 80 mmol/kg diet; 4-HPR, 4 and 2 mmol/kg diet) or by subcutaneous injection twice a week (beta-CT, 32 and 16 mg/kg b.w.). Mice were treated with a single i.p. dose of 10 micromol 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 < 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 adenocarcinomas were accompanied by corresponding increases in adenomas in these treatment groups. Thus, this study showed that FA, NAC, 4-HPR and beta-CT did not inhibit the total tumor formation, however, at the higher doses both NAC and beta-CT significantly retarded the malignant progression in the lung of NNK-treated A/J mice.
Conaway
C C
CC
Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, NY 10595, USA.
Jiao
D
D
Kelloff
G J
GJ
Steele
V E
VE
Rivenson
A
A
Chung
F L
FL
D000111:Acetylcysteine / Q000627:therapeutic use; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017313:Fenretinide / Q000627:therapeutic use; D005650:Fumarates / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines / Q000633:toxicity*; D010947:Plants, Toxic; D014026:Nicotiana / Q000737:chemistry; D019207:beta Carotene / Q000627:therapeutic use
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D005650:Fumarates; D009602:Nitrosamines; D019207:beta Carotene; D017313:Fenretinide; C032005:fumaric acid; D000111:Acetylcysteine