Effects of N‐acetylcysteine in an esophageal carcinogenesis model in rats treated with diethylnitrosamine and diethyldithiocarbamate

Abstract

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 4.9؋ 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 DENinduced esophageal carcinogenesis by DEDTC and the protective effects of NAC are discussed.

Effect of antioxidant phytochemicals on the hepatic tumor promoting activity of 3,3′,4,4′-tetrachlorobiphenyl (PCB-77)

“…In other liver carcinogenesis models, NAC (10–100 mg/kg body weight p.o. 5x/wk) inhibited the induction of PGST-positive foci by 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in rats (Nishikawa-Ogawa et al , 2006), but did not affect the induction of liver tumors in rats treated with DEN and diethyldithiocarbamate when administered at 400 mg/kg body weight/day in drinking water (Balansky et al , 2002). Resveratrol, injected at a dose of 1 mg/kg body weight/day i.p.…”

“…The phytochemicals selected for this study were ellagic acid, β-carotene, curcumin, N-acetyl cysteine (NAC), coenzyme Q 10 (CoQ10), resveratrol, lycopene, and a tea extract containing epigallocatechin-3-gallate (EGCG). All of these agents have been found to inhibit experimental carcinogenesis in several studies (Wood et al , 1982; Mukhtar et al , 1986; Suzuki et al , 1986; Toma et al , 1995; Yang et al , 2001; Balansky et al , 2002; Nishino et al , 2002; Yang et al , 2002; Hannum, 2004; Joe et al , 2004; Russell, 2004; Bhuvaneswari and Nagini, 2005; Perumal et al , 2005; Nishikawa-Ogawa et al , 2006; Sakano et al , 2006; Thangapazham et al , 2006). Ellagic acid is a naturally occurring plant phenol that has strong scavenging ability for hydrogen peroxide, superoxide anion and hydroxy anion in vitro (Cozzi et al , 1995; Iino et al , 2001).…”

Reduction of estrogen-induced transformation of mouse mammary epithelial cells by N-acetylcysteine

“…Thus, N-acetylcysteine has desirable properties for long-term use. The discovery that N-acetylcysteine can prevent mutagenesis by oxidative DNA damage [27][28][29] and decrease the incidence of pre-neoplastic and neoplastic lesions by various smoke-related chemical carcinogens in rodents [23,[30][31][32] pointed to its chemopreventive potential. Unfortunately, clinical trials did not indicate Nacetylcysteine to be effective in preventing lung cancer in smokers [33].…”

Chemopreventive effects of tolfenamic acid against esophageal tumorigenesis in rats

“…It was shown that N-nitroso compounds and their precursors are among the etiological factors for SCC in the SCC-dominated areas. Nitrosamines have very high organ specificity and have been used as tumor inducing agents in several murine models [6,[9][10][11]. N-nitrosomethylbenzylamine (NMBA) is a potent esophageal carcinogen in rats [12].…”