Inhibition of DNA synthesis by carcinogens in human colon mucosa in organ culture

Abstract

The capability of carcinogens with different modes of action to affect replicative DNA synthesis in the human colon was tested with the use of organ culture of histologically normal mucosae from patients undergoing colectomy for colon cancer or diverticulosis. 1,2-Dimethylhydrazine, an organotropic carcinogen for the colon in rodents, inhibited DNA synthesis of mucosa at a concentration of 3.0 mM but not at 1.5 mM. Methylazoxymethanol acetate, a proximate carcinogen, inhibited DNA synthesis at a concentration of 1.5 mM. N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG), a direct-acting carcinogen, inhibited DNA synthesis at a concentration of 0.5 mM. No tissue toxicity was observed at the doses of these carcinogens used. The procarcinogen benzo[a]pyrene, which is not organotropic for the colon, caused no inhibition of DNA synthesis in colon explants at concentrations of 0.01--0.05 mM. These data indicate that replicative DNA synthesis in the human colon is most sensitive to the inhibitory effect of the direct-acting carcinogen MNNG.