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Persistence of DNA Damage during Development of Liver Angiosarcoma in Rats Fed Dimethylnitrosamine¹

Fels Research Institute [S.E.A., E.F., D.S.R.S.], and Departments of Biochemistry [S.E.A. E.F.] and Pathology [E.F., D.S.R.S.], Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Chronic feeding of a diet containing dimethylnitrosamine (50 ppm) to rats resulted in liver DNA damage monitored as slow sedimentation of the DNA compared to that of the control in alkaline sucrose gradients. The damage in rat liver DNA could be seen within 2 days after beginning the feeding of diets containing the carcinogen and was progressive with the time of feeding, up to 8 weeks. Extended feeding up to 15 or 31 weeks did not result in a proportionate increase in the damage to the DNA. The DNA damage observed at 8 weeks persisted until 31 weeks, at which time liver angiosarcoma was present. Despite the fact that the DNA damage induced by dimethylnitrosamine appears to involve the bulk of the liver DNA, the tumors developed were entirely from vascular endothelium. The implication of these results in the initiation of carcinogenesis is discussed.

¹ Supported in part by USPHS Grants CA-12218, CA-12227, and CA-14689 from the National Cancer Institute and AM-14482 from the National Institute of Arthritis, Metabolism and Digestive Diseases.

² Present address: Department of Pathology, University of Toronto, Medical Sciences Building, Toronto, Ontario M5S 1A8, Canada.

³ To whom requests for reprints should be addressed.

Received 11/21/77. Accepted 2/ 8/79.