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Intestinal cancer induced by N-nitroso compounds
1NCI-Frederick Cancer Research Facility, BRI-Basic Research Program, Maryland 21701.
Abstract:
Several N-nitroso compounds induce tumors of the colon, and some induce tumors in other parts of the intestinal tract as well. The nitrosamines that induce colon tumors are beta oxidized n-propyl-nitrosamines. These require metabolic activation, as do 1,2-dimethylhydrazine, azomethane, and azoxymethane, another group of colon carcinogens. Several nitrosoalkylureas induce tumors in rat colons after oral administration, although the monoalkylnitrosoureas are fairly unstable and might not be expected to reach the colon. However, monoalkylnitrosoureas are equally effective with the much more stable dialkylnitrosoureas. Although nitrosomethylurea did not induce colon tumors under these conditions, nitrosoethylurea did, together with nitrosodiethylurea and other nitrosoethylalkylureas. Nitroso-n-butyl-, n-amyl-, n-hexyl-urea, and nitrosohydroxyethylurea also induced colon tumors, but the last, like nitrosoethylurea, also induced tumors of the duodenum and ileum. In most of these experiments male rats were more susceptible to induction of intestinal tumors than female rats. An explanation for the differences between these compounds of similar structure might be found in variations in their ability to alkylate DNA in intestinal cells, or in differences in stability of the alkylated product between the compounds. The physical properties of the compounds might also modulate the process of carcinogenesis, however.
Insights
Several N-nitroso compounds cause colon tumors in rats, requiring metabolic activation. Differences in DNA alkylation and compound stability may explain varying carcinogenic effects and tumor locations.
Area of Science:
- Toxicology
- Carcinogenesis
- Organic Chemistry
Background:
- N-nitroso compounds are known carcinogens.
- Specific N-nitroso compounds induce tumors in the colon and other intestinal regions.
- The mechanism of action for these compounds involves metabolic activation.
Purpose of the Study:
- To investigate the carcinogenic potential of various N-nitroso compounds on the rat intestinal tract.
- To explore structure-activity relationships in N-nitroso compound-induced carcinogenesis.
- To identify factors influencing tumor induction sites and susceptibility.
Main Methods:
- Oral administration of various N-nitroso compounds to rats.
- Observation and documentation of tumor development in the colon and other intestinal segments.
- Comparison of carcinogenic effects between different N-nitroso compounds and sexes.
Main Results:
- Beta-oxidized n-propyl-nitrosamines, 1,2-dimethylhydrazine, azomethane, and azoxymethane are potent colon carcinogens requiring metabolic activation.
- Nitrosoalkylureas, including monoalkyl- and dialkylnitrosoureas, induced colon tumors.
- Nitrosoethylurea and nitrosohydroxyethylurea also induced tumors in the duodenum and ileum.
- Male rats exhibited higher susceptibility to intestinal tumor induction than females.
Conclusions:
- Carcinogenicity of N-nitroso compounds is influenced by their chemical structure, metabolic activation, and DNA alkylating ability.
- Compound stability and physical properties may modulate the carcinogenic process.
- Sex-based differences in susceptibility to intestinal carcinogenesis were observed.
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