In two series of experiments female rats (Sprague-Dawley) were given periodically 8 mg/kg diethylnitrosamine (DENA) for ten weeks. The controls received 8 mg/kg thioacetamide (TAA). After four weeks islands of cells lacking glucose-6-phosphatase appeared in rats treated with DENA, whereas no islands were found in TAA-treated rats even after two weeks. In contrast, both agents cause clear areas around the central vein which then disappear a few weeks later. In one series female rats received 8 mg/kg DENA daily for one week. The animals were then examined after prolonged intervals. Even after 210 days several islands were found, indicating a total dose of 56 mg/kg is sufficient to form islands that remain. In one animal a micro-carcinoma was found. In a second series DENA was administreed at 8 mg/kg for eight weeks and then stopped to investigate the growth of the islands after remission of reversible changes. For five weeks the islands did not grow but then suddenly turn into carcinomas. Histochemical reactions within a carcinoma are generally uniform, but usually different from carcinoma to carcinoma, also within the same animal. All possible combinations of losses of glucose-6-phosphatase and ATPase activities, and of the tissue specific antigens of microsomes are found among the various tumors. To interpret the results it is assumed that several somatic mutations are necessary to produce a liver carcinoma with DENA. Through selection, only those mutants accumulate that raise the rate of cell division of the hepatocytes, as opposed to lengthening the life-span of the cells. With this assumption one can explain the characteristic localization of the islands of cells in a sector of the central vein. © 1969 Springer-Verlag.
