DISTURBANCE OF THE CELL-CYCLE WITH COLCHICINE ENHANCES THE GROWTH ADVANTAGE OF DIETHYLNITROSAMINE-INITIATED HEPATOCYTES IN RATS

The effect of cell cycle disturbance due to colchicine on the inductio n of enzyme-altered foci during liver regeneration in rats was studied . For initiation, diethylnitrosamine (DEN) at a dose of 10 mg/kg was i njected intraperitoneally and partial hepatectomy (PH) was performed 4 h thereafter. Colchicine at doses of 0, 0.1, 0.25 and 0.5 mg/kg was i njected intraperitoneally 1 and 3 days after the initiation, followed by application of selection pressure consisting of 2-acetylaminofluore ne (AAF) and carbon tetrachloride (CCl4) administration. As end point lesions, gamma-glutamyltransferase (GGT)-positive enzyme-altered foci were assayed at week 5. There was no significant effect of colchicine on numbers of foci. However, a significant, dose-dependent increase in the area of GGT-positive lesions in the groups treated with colchicin e was observed. Bromodeoxyuridine labeling indices were higher in foci induced in colchicine-treated rats than in the untreated rats. In a s eparate experiment, serum glutamic pyruvic transaminase was not increa sed significantly after DEN and colchicine treatment, and the mitotic index at 6 days after PH was increased in the liver of colchicine-trea ted rats. These results suggest that the cell cycle disturbance induce d by colchicine causes more pronounced selective growth of cells initi ated by DEN and colchicine, and this experimental model may be useful for analyzing the mechanisms underlying that growth advantage and the effects of cell cycle abnormalities in liver carcinogenesis.