Colon cancer: Its epidemiology and experimental production

Abstract

Evidence from epidemiology and geographic pathology indicates that colon cancer is an environmental disease. Large bowel cancer currently has the highest incidence of all human neoplastic diseases in the United States. In other Western countries it has similarly high incidences, while in countries on the African continent, in Central and Western Latin America, and in Japan, it has a low incidence. In low incidence countries, the incidence of the disease is inversely related to level of socioeconomic group; such a distinction is not observed in the Western world. High intake of dietary fat is considered the key element associated with higher risk. Dietary fiber content has been implicated but requires validation. Studies in metabolic epidemiology have shown that individuals on high fat diets have slightly different intestinal microflora. However, in both high and low risk individuals significantly different levels of certain key bacterial enzymes in the flora are even more important. There are appreciable differences in neutral sterols and bile acids, the high risk population having higher levels in their stools. Reliable modalities for the induction of large bowel cancer in animal models include the administration to rodents of derivatives of: 1) 3-methyl-4-aminobiphenyl; 2) compounds related to the natural plant product cycasin or methylazoxymethanol β-glucoside, namely methylazoxymethanol acetate, azoxymethane (AOM), and 1,2-dimethylhydrazine (DMH); 3) intrarectal administration of direct-acting carcinogens such as methylnitro-nitrosoguanidine (MNNG), methylnitrosourea, and methylazoxymethanol acetate; and 4) in select hamster strains, oral administration of large amounts of 3-methylcholanthrene. Some of these chemicals, specifically intrarectal MNNG or AOM, are at least as carcinogenic in germ-free rats as in conventional rats, but 1,2-dimethylhydrazine is less active in the germ-free system. A high fat diet, similar to that of a high risk human population, yields more induced colon cancer compared with a low fat diet. Animals on a high fat diet excrete more neutral sterols and bile acids than controls. Colon cancer induced by DMH in animals can be inhibited with drugs such as disulfiram, which alter the metabolic fate of the carcinogen. Bile acids exert a promoting effect in colon carcinogenesis in animal models, thus outlining the possible role of bile acids in human cancer development.