Effect of chronic dietary ethanol consumption on the initiation and promotion of chemically-induced esophageal carcinogenesis in experimental rats.
Preliminary dose finding studies showed that 22 mg/kg of N-nitrosomethylbenzylamine (NMBZA) delivered over 5 days did not induce esophageal lesions, but 18 mg/kg administered over a period of 2 or 3 weeks did induce these lesions. Based on these results, Sprague-Dawley rats were treated with 2.5 mg/kg NMBZA three times a week for 3 weeks to initiate esophageal carcinogenesis. The experimental animals were administered isocaloric ethanol diet either before and during NMBZA initiated carcinogenesis, or after initiation as a tumor promoter. The esophagi of rats that died or who were terminated at 18 months of age were examined for nodules and tumors. When ethanol was administered before and during initiation, the mean frequency of esophageal lesions was 8.04 +/- 3.04/rat with an average size of 1.44 +/- 0.27 mm versus 12.41 +/- 2.12/rat and 0.92 +/- 0.17 mm respectively for the controls. Only three out of 13 of the ethanol-fed rats had tumors (mainly squamous papillomas) versus 10 out of 26 of the control-fed animals. Ethanol consumption before and during initiation, therefore, decreased the incidence of esophageal nodules and tumors. With ethanol administered as a promoter, on the other hand, while incidence of the total lesions was not affected appreciably, the incidence of tumors was remarkably increased. With ethanol promotion the mean frequency of lesions was 8.75 +/- 1.07/rat with an average size of 1.02 +/- 0.09 mm versus 10.94 +/- 1.49/rat and 1.32 +/- 0.13 mm respectively for the controls. In this case, the ethanol-consuming rats had tumors in 14 out of 75 animals versus one small tumor in 32 of the controls. The results indicate that the occurrence of esophageal tumors is inhibited by simultaneous ethanol administration, but promoted when ethanol is administered post-initiation ostensibly by allowing extensive dysplastic proliferation of the carcinogen-induced lesions.
Mufti
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Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson 85721.
Becker
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Sipes
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D000818:Animals; D002273:Carcinogens; D003043:Cocarcinogenesis; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives*; D004938:Esophageal Neoplasms / Q000139:chemically induced* / Q000473:pathology; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D002273:Carcinogens; D000431:Ethanol; C014707:nitrosobenzylmethylamine; D004128:Dimethylnitrosamine