Experimental chemical
carcinogenesis in the digestive tract is reviewed, mainly on the basis of information obtained in the laboratories of the National
Cancer Center Research Institute. It is generally accepted that
cancer 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 be produced 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 resistant and this is a dominantly inherited trait. Genes responsible for the sensitivity to
gastric cancer induction are at present under 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 significance. 2-Amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine (
PhIP), one of the most abundant, causes
colon cancers in male rats, whereas in females it induces breast
cancers. The
colon cancers induced by
PhIP feature a deletion of G as represented by 5-GGGA-3-->5-GGA-3 in the Apc gene, resulting in a truncated Apc molecule. Microsatellite mutations have also been found in
PhIP-induced colon
tumors, as in human hereditary non-polyposis
colorectal cancer cases. Similarly to the case of
gastric cancer production by
MNNG, there is a genetic component and F344 rats are more susceptible to
PhIP colon
carcinogenesis than the ACI/N strain and the gene responsible is being sought. Since
carcinogenesis proceeds with accumulation of genetic alteration, often involving
genomic 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.