EFFECTS OF DELAYS IN THE CELL-CYCLE ON THE INDUCTION OF PRENEOPLASTIC AND NEOPLASTIC LESIONS IN RAT-LIVER BY 1,2-DIMETHYLHYDRAZINE

  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (3) , 876-880
Abstract
The relationship was explored between cell proliferation and the induction of early putative preneoplastic lesions by carcinogens. Rats were given a nonnecrogenic dose of 1,2-dimethylhydrazine 24 h before being subjected to partial hepatectomy. Beginning 4 h later, hydrocortisone was injected 10 times at 4-h intervals to delay progression through the cell cycle, including inhibition of DNA synthesis by at least 85% for about 40 h. At the appropriate time therafter, the putative preneoplastic hepatocytes were selectively stimulated to grow in vivo into .gamma.-glutamyltransferase-positive focal lesions. Animals given hydrocortisone showed a large decrease (71%) in the number of .gamma.-glutamyl-transferase-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 h or 1 wk thereafter. A significant number of .gamma.-glutamyltransferase-positive foci was found when partial hepatectomy was performed at 12 or 24 h but far fewer were found when the operative partial hepatectomy was delayed to 48 h or 1 wk later. Similarly, in long-term experiments, 6 of 14 animals developed primary hepatocellular carcinoma 13 mo. after the time of injection of 1,2-dimethylhydrazine when partial hepatectomy was performed at 12 h, while none of the animals developed liver cancer when the operation was performed at 48 h. 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.