Experimental chemical carcinogenesis in the stomach and colon

Experimental chemical carcinogenesis in the digestive tract is reviewed,mainly on the basis of information obtained in the laboratories of theNational Cancer Center Research Institute. It is generally accepted thatcancer is the outcome of DNA damage, resulting in mutation, loss,amplification and recombination of genes. Gastric cancer is no exception.It was shown very early that cancer of the glandular stomach can beproduced in rats by administration of N-methyl-N'-nitro-N-nitrosoguanidine(MNNG), a widely used mutagen. However, this depends on the genotype.Whereas the ACI rat is susceptible to MNNG, the Buffalo rat is resistantand this is a dominantly inherited trait. Genes responsible for thesensitivity to gastric cancer induction are at present under investigationby linkage analysis of rat genome markers. With regard to cancer in humans,our finding that cooked proteinaceous foods can give rise to a series ofheterocyclic amines (HCAs) is of major significance.2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the mostabundant, causes colon cancers in male rats, whereas in females it inducesbreast cancers. The colon cancers induced by PhIP feature a deletion of Gas represented by 5-GGGA-3-->5-GGA-3 in the Apc gene, resulting in atruncated Apc molecule. Microsatellite mutations have also been found inPhIP-induced colon tumors, as in human hereditary non-polyposis colorectalcancer cases. Similarly to the case of gastric cancer production by MNNG,there is a genetic component and F344 rats are more susceptible to PhIPcolon carcinogenesis than the ACI/N strain and the gene responsible isbeing sought. Since carcinogenesis proceeds with accumulation of geneticalteration, often involving genomic instability, exposure to any kind ofcarcinogenic substances, either xeno- or autobiotics, needs to be reducedas far as possible, taking account of inconvenience at the individual andsocio-economical levels.