nsc-141537 and nitrosobenzylmethylamine

Epidemiological evidence from China and South Africa has implicated Fusaria mycotoxins in the etiology of esophageal cancer, although treatment of animals with extracts of Fusaria cultures did not cause cancer of the esophagus. Fusaria are the major producers of trichothecenes, and animal experiments have shown that these mycotoxins can damage the esophagus but they have not been shown to cause esophageal cancer. A plausible concept is therefore that esophageal cancer is initiated by the potent environmental esophageal carcinogens, certain nitrosamines, but that the levels of exposure are too low to cause clinical cancer unless their effects are enhanced by additional risk factors. Among the most likely enhancing factors in the regions mentioned above are Fusaria mycotoxins. As trichothecenes are known to inhibit sulphydryl-dependent reactions and to inhibit protein synthesis, experiments were carried out to determine whether potentiation of cancer could be mediated via inhibition of the DNA repair protein O6-methylguanine-DNA methyl transferase (O6MG-MT). The effect of diacetoxyscirpenol (DS) on O6MG-MT was studied. Chronic or acute treatment with DS did not alter the level of O6MG-MT in esophagus, or affect the depletion which occurs after injection of methylbenzylnitrosamine, or alter the rate of reappearance of O6MG-MT. A high dose of DS induced O6MG-MT in liver. These results suggest that if trichothecenes are risk factors for esophageal cancer, the effect is unlikely to be mediated by inhibition of O6MG-MT. Induction of the repair protein in liver may be relevant in the animal toxicoses caused by consumption of trichothecenes, but is unlikely to be implicated in the etiology of liver cancer in man.

Topics: Animals; Cocarcinogenesis; Dimethylnitrosamine; DNA Ligases; Enzyme Induction; Esophageal Neoplasms; Esophagus; Female; Fusarium; Liver; Mycotoxins; Polynucleotide Ligases; Rats; Rats, Inbred Strains; Sesquiterpenes; Trichothecenes

To test the concept that human oesophageal cancer is initiated by nitrosamines and potentiated by consumption of food contaminated by mycotoxins produced by Fusaria, the effect of the trichothecene mycotoxin diacetoxyscirpenol (DS), alone and in combination with N-nitroso-N-methylbenzylamine (NMBzA), on rat oesophagus was studied. Chronic treatment with DS induced oesophageal hyperplasia, but simultaneous treatment with NMBzA tended to inhibit rather than to enhance carcinogenesis. The mycotoxin did not inhibit O6-alkylguanine-DNA alkyltransferase in oesophagus and produced a marked induction of repair protein in liver. Depletion of the repair protein in oesophagus brought about by injection of NMBzA was not inhibited by the mycotoxin, and its reappearance was not delayed. Intubation of DS reduced DNA synthesis in the oesophagus, while dietary treatment resulted in an increase after nine weeks. The results suggest that, while simultaneous treatment with DS reduces cancer induced by NMBzA, if there is first exposure to mycotoxin and induction of hyperplasia, and then exposure to nitrosamine, so that the carcinogen acts on a vulnerable oesophagus in which there is an increased rate of cell proliferation, the mycotoxin could well enhance carcinogenesis.

Topics: Animals; Dimethylnitrosamine; Esophageal Neoplasms; Esophagus; Liver; Nitrosamines; Rats; Sesquiterpenes; Trichothecenes

The fact that the only chemicals known to be potent carcinogens for the esophagus in animals are certain nitrosamines suggests that these environmental carcinogens could be a cause of human esophageal cancer. Epidemiological investigations support this concept. The level of exposure alone is not considered sufficient to account for the very high incidence of the disease in certain regions, but potentiating factors have been shown to have a dramatic effect on nitrosamine-induced esophageal cancer in animal experiments. A likely enhancing factor is consumption of food contaminated by molds, especially by Fusaria spp, a group known to produce trichothecene mycotoxins. The effect of simultaneous treatment with diacetoxyscirpenol (DS) on methyl-benzyl-nitrosamine (NMBzA)-induced esophageal cancer was studied. Feeding a diet containing DS at 10 ppm for 10 weeks caused thickening of the basal cell layer of the esophageal epithelium, but feeding DS (10 ppm) simultaneously with NMBzA (4, 8, 16 ppm) for 10 weeks, or feeding a lower dose of DS with NMBzA for a longer period, or administration of DS per os at intervals during NMBzA treatment, did not potentiate but possibly reduced esophageal tumors. Toxicity, revealed by reduced growth rate of DS-fed animals, may have inhibited carcinogenesis. In contrast to the rapid potentiating effect of zinc deficiency, DS does not appear to cause an early enhancement of esophageal cancer.

Topics: Animals; Cocarcinogenesis; Dimethylnitrosamine; Esophageal Neoplasms; Female; Mycotoxins; Rats; Rats, Inbred Strains; Sesquiterpenes; Trichothecenes