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Effects of Delays in the Cell Cycle on the Induction of Preneoplastic and Neoplastic Lesions in Rat Liver by 1,2-Dimethylhydrazine¹

Department of Pathology, University of Toronto, Toronto, Ontario, Canada M5G 1L5

This study was designed to explore further the relationship between cell proliferation and the induction of early putative preneoplastic lesions by carcinogens. Rats were given a non-necrogenic dose of 1,2-dimethylhydrazine 24 hr before being subjected to partial hepatectomy. Beginning 4 hr later, hydrocortisone was injected 10 times at 4-hr intervals to delay progression through the cell cycle, including inhibition of DNA synthesis by at least 85% for about 40 hr. At the appropriate time thereafter, the putative preneoplastic hepatocytes were selectively stimulated to grow in vivo into -glutamyltransferase-positive focal lesions. Animals given hydrocortisone showed a large decrease (71%) in the number of -glutamyltransferase-positive foci. In contrast, when hydrocortisone was given at 6 days after partial hepatectomy, no inhibition in the induction of hepatic lesions was observed. In the next experiments, rats were treated with 1,2-dimethylhydrazine and were subjected to partial hepatectomy at 12, 24, or 48 hr or 1 week thereafter. A significant number of -glutamyltransferase-positive foci was found when partial hepatectomy was performed at 12 or 24 hr but far fewer were found when the operative partial hepatectomy was delayed to 48 hr or 1 week later. Similarly, in long-term experiments, six of 14 animals developed primary hepatocellular carcinoma 13 months after the time of injection of 1,2-dimethylhydrazine when partial hepatectomy was performed at 12 hr, while none of the animals developed liver cancer when the operation was performed at 48 hr. These results imply that the majority of biochemical lesions induced by 1,2-dimethylhydrazine that are relevant to the induction of liver preneoplasia and neoplasia are short-lived and that their persistence is associated with some cellular activity closely related to the cell cycle.

¹ This research was supported by grants from the National Cancer Institute of Canada; National Cancer Institute, NIH (CA 21157, CA 23958); and Medical Research Council of Canada (MT 5994).

² Recipient of M. R. C. Studentship from the Medical Research Council of Canada (1975 to 1979). To whom requests for reprints should be addressed.

³ Present address: Department of Pathology, Sapporo Medical College, S.1, W.17 Chuo-ku, Sapporo, Japan 060.

Received 7/20/81. Accepted 12/ 2/81.

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