Colorectal carcinogenesis

Evidence derived from migrant populations suggesting that colorectal cancer is induced by environmental carcinogens has intensified the search for specific agents that may cause this neoplasm in the human population, and dietary constituents have become prime suspects. Since information about induction must be acquired in part from animal models, examination of responses in laboratory animals is a feature necessary for delineating etiology. They have provided information not only about binding, possible direct action on target epithelium, and differential activity of enzyme systems, but also details about pathways for metabolic activation. For example, the action of bacterial flora is required for conversion of cycasin and dimethylhydrazine to the active azoxy compound, and the liver is responsible for N‐hydroxylation and conjugation of aminodiphenyls before their entry via the bile into the alimentary tract where bacteria may possibly be involved in conversion to active compound. Thus, adducts and proximal carcinogens often constitute the distal portion of a metabolic chain of events in which not only colonic epithelium but flora of the gut and the liver may participate. The carcinogens known to induce colorectal neoplasms will be reviewed, ranging from the unknown constituent of bracken fern to N‐methyl‐N′‐nitro‐N‐nitrosoguanidine which is effective on local application, along with a summary of biochemical pathways known to be operative in laboratory animals. The implications of this information for human disease will then be discussed. Hopefully, the mechanisms for induction of colorectal cancer in laboratory animals with carcinogens that correlate well with human exposure will ultimately provide the means to determine which exogenous carcinogens, which metabolic routes, which of the flora, and which endogenous products participate in the induction of clinical adenocarcinoma of the colon and rectum.