EXPERIMENTAL CHEMICAL CARCINOGENESIS IN THE STOMACH AND COLON

Experimental chemical carcinogenesis in the digestive tract is reviewe d, mainly on the basis of information obtained in the laboratories of the National Cancer Center Research Institute. It is generally accepte d that cancer is the outcome of DNA damage, resulting in mutation, los s, amplification and recombination of genes. Gastric cancer is no exce ption. It was shown very early that cancer of the glandular stomach ca n be produced in rats by administration of N-methyl-N'-nitro-N-nitroso guanidine (MNNG), a widely used mutagen. However, this depends on the genotype. Whereas the ACI rat is susceptible to MNNG, the Buffalo rat is resistant and this is a dominantly inherited trait. Genes responsib le for the sensitivity to gastric cancer induction are at present unde r investigation by linkage analysis of rat genome markers. With regard to cancer in humans, our finding that cooked proteinaceous foods can give rise to a series of heterocyclic amines (HCAs) is of major signif icance. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the most abundant, causes colon cancers in male rats, whereas in fema les it induces breast cancers. The colon cancers induced by PhIP featu re a deletion of G as represented by 5-GGGA-3-->5-GGA-3 in the Ape gen e, resulting in a truncated Ape molecule. Microsatellite mutations hav e also been found in PhIP-induced colon tumors, as in human hereditary non-polyposis colorectal cancer cases. Similarly to the case of gastr ic cancer production by MNNG, there is a genetic component and F344 ra ts are more susceptible to PhIP colon carcinogenesis than the ACI/N st rain and the gene responsible is being sought. Since carcinogenesis pr oceeds with accumulation of genetic alteration, often involving genomi c instability, exposure to any kind of carcinogenic substances, either xeno- or autobiotics, needs to be reduced as far as possible, taking account of inconvenience at the individual and socio-economical levels .