Effects of N-acetylcysteine in an esophageal carcinogenesis model in rats treated with diethylnitrosamine and diethyldithiocarbamate.
Due to the increasing role of esophageal tumors in human cancer pathology, there is need for animal models evaluating the mechanisms of esophageal carcinogenesis and investigating protective factors toward this disease. Several N-nitrosamines have been shown to induce esophageal tumors in rats. We designed a study in BD(6) rats treated with N-diethylnitrosamine (DEN) according to a simple protocol involving weekly i.p. injections of this carcinogen for 8 consecutive weeks. This treatment resulted in a high incidence and multiplicity of liver tumors and in occurrence of preneoplastic lesions and papillomas in the esophagus. Intraperitoneal injections of diethyldithiocarbamate (DEDTC), 4 hr after each DEN injection, i.e., during the period of DEN metabolization, improved survival of rats and did not affect the liver tumor yield but doubled the incidence of esophageal tumors and enhanced 4.9x their multiplicity. Moreover, 15% of rats developed esophageal squamocellular carcinomas. The oral administration of the thiol N-acetyl-L-cysteine (NAC), a precursor and analogue of reduced glutathione, to rats treated with the DEN/DEDTC combination did not change the liver tumor yield but attenuated esophageal carcinogenesis by producing a significant shift of preneoplastic lesions to milder forms as well as a significant decrease of tumor multiplicity. Therefore, the DEN/DEDTC protocol appears to provide an interesting 2-organ model of N-nitrosamine-induced carcinogenesis in rats, in which NAC is moderately effective as an inhibitor. The mechanisms underlying enhancement of DEN-induced esophageal carcinogenesis by DEDTC and the protective effects of NAC are discussed.
Balansky
Roumen M
RM
National Center of Oncology, Sofia, Bulgaria.
Ganchev
Gancho
G
D'Agostini
Francesco
F
De Flora
Silvio
S
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D004052:Diethylnitrosamine / Q000008:administration & dosage*; D004050:Ditiocarb / Q000008:administration & dosage*; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D004947:Esophagus / Q000187:drug effects / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006965:Hyperplasia; D007642:Keratosis; D008113:Liver Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011919:Rats, Inbred Strains; D015996:Survival Rate
D016166:Free Radical Scavengers; D004052:Diethylnitrosamine; D004050:Ditiocarb; D000111:Acetylcysteine