Influence of disulfiram on the organotropy of the carcinogenic effect of dimethylnitrosamine and diethylnitrosamine in rats

Abstract

In former studies in rats and mice it was shown that the acute toxicity of dimethylnitrosamine (DMNA) and diethylnitrosamine (DENA) is reduced by additional treatment with tetraethylthiuramdisulfide [(Disulfiram, Antabus (DSF)]. In long-term experiments in 40 rats given 500 mg/kg DSF/week the substance did not show carcinogenic effects, however, influenced the action of the nitrosamines. DENA, which was administered to 38 rats in a dosage of 20 mg/kg/week, induced liver tumors in 90% of the animals; in 29% besides some precancerous stages predominantly malignant carcinomas of the oesophagus were seen. DMNA when given to 31 rats in a dosage of 4 mg/kg/week induced liver tumours in 55% of the animals. 26 rats were treated with a combination of 500 mg/kg DSF/week and 20 mg/kg DENA/week. In only 31% of the animals of this group liver tumors were found, however, 81% of them besides some precancerous stages showed predominantly carcinomas of the oesophagus. The combination of 500 mg/kg DSF/week and 4 mg/kg DMNA/week induced only 1 liver tumor (=3%) out of a group of 29 animals, whereas 59% of them showed squamous cell carcinomas of the paranasal sinus that were not seen when DMNA was given alone.

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

“…In most cases, their influence on carcinogenicity is inhibitory. Caution must however be exerted not to become too optimistic about antioxidants in the diet because there is an example where the carcinogenic activity of dimethylnitrosamine or diethylnitrosamine was shifted from the liver to other argans under the combined treatment with disulfiram [233]. This antioxidant has probably led to a prolonged presence of unmetabolized nitrosamine in the blood so that argans other than the liver increased their activity with respect to the oxidation of the carcinogen.…”

Anticancer activity and chemoprevention of xenobiotic organosulfurs in preclinical model systems

“…It resurfaced within 10–15 years as a means to control chemical carcinogenic-induced tumors in rodents. It: (a) completely prevented the occurrence of benzo[a]pyrene (BP) induced tumors in the fore-stomach of Ha/ICR female mice terminated at 29 weeks but did not alter induction of pulmonary adenoma formation in A/HeJ female mice at 31 weeks [28]; (b) completely prevented 1,2-dimethylhydrazine-(DMH-) induced tumors of the large intestine of CF1 mice at 36 weeks [84]; (c) reduced liver tumors (66% and 95%) induced in rats by either diethylnitrosamine (DENA) or dimethylnitrosamine (DMNA) [85]; (d) prevented liver tumors, had no effect on esophageal and urinary bladder tumors, and actually increased lung tumors from 0% to 30% in rats, all induced by N-nitrosodibutylamine (NDBA) [86], and (e) reduced urinary bladder cancer from 100% to 13% in rats given N-n-butyl-N(4-hydroxybuty)nitrosamine (BHBN) [87]. Surprisingly, when co-administrated with (a) DMNA, cell carcinomas of the paranasal sinus that were not found when either was given alone increased [88], and (b) NDBA, formation of lung tumors not normally induced by either individually were found [86].…”

Sugar-Linked Dithiocarbamates as Modulators of Metabolic and Genotoxic Properties of N-Nitroso Compounds

“…Compound 5a activated GR by 47.9% ± 4.9% (p <0.001) (4 h) and 82.0% ± 5.3% (p <0.001) (24 h) compared to the control group and led to a 2-fold increase in GST activity. GSH content was decreased 0 Inhibitors (1.5 mmoLkg, ip) were administered 1 h before and 5 h after the treatment of [14C]NDEA (28 mgkg, 5 «Ci/kg, ip). 6 Values represent percentage of the given dose.…”

“…4 In the case of N-nitrosodiethylamine (NDEA) and V-nitrosodimethylamine (NDMA), DSF leads to a shift in the organotropy of tumor induction. 5 The mechanisms by which these compounds modulate toxic and carcinogenic properties of chemical carcinogens are well investigated with regard to some nitrosamines: (i) DSF and DDTC inhibit the mixed function oxidase system.6•7 Treatment of rats exposed to nitrosamine with DSF or DDTC caused a diminished production of carcinogen-derived CO2 and increased the elimination of non-metabolized nitrosamine in the urine. 8 The inhibition of metabolism results in a reduction of nitrosamine-induced alkylation8 and strand breaks of rat liver DNA and RNA.9•10 (ii) DSF increases glutathione contents and detoxifying phase II enzymes like glutathione S-transferase (GST)11 •12 and UDP-glucuronyl transferase.…”