Disturbance of the Cell Cycle with Colchicine Enhances the Growth Advantage of Diethylnitrosamine‐initiated Hepatocytes in Rats

Abstract

The effect of cell cycle disturbance due to colchicine on the induction of enzyme‐altered foci during liver regeneration in rats was studied. For initiation, diethylnitrosamine (DEN) at a dose of 10 mg/ kg was injected 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 injected intraperitoneally 1 and 3 days after the initiation, followed by application of selection pressure consisting of 2‐acetylaminofluorene (AAF) and carbon tetrachloride (CCl4) administration. As end point lesions, γ–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 colchicine was observed. Bromodeoxyuridine labeling indices were higher in foci induced in colchicine‐treated rats than in the untreated rats. In a separate experiment, serum glutamic pyruvic transaminase was not increased significantly after DEN and colchicine treatment, and the mitotic index at 6 days after PH was increased in the liver of colchicine‐treated rats. These results suggest that the cell cycle disturbance induced by colchicine causes more pronounced selective growth of cells initiated 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.

Alterations of the Transforming Growth Factor‐(β Signaling Pathway in Hepatocellular Carcinomas Induced Endogenously and Exogenously in Rats

“…With the exogenous agent, the method for the production of HCCs was as previously described. 3,4) Animals received DEN intraperitoneally at a dose of 10 mg/ kg body weight followed after 4 h by PH performed by the method of Higgins and Anderson. 40) Colchicine at a dose of 0.5 mg/kg body weight was injected intraperitoneally 1 and 3 days after DEN treatment.…”

“…We have reported that a cell cycle disturbance induced in DEN-initiated hepatocytes by colchicine gives a growth advantage to formation of putative preneoplastic lesions under conditions of partial hepatectomy (PH) and selection pressure, so that a high incidence of HCCs can be obtained within a short period. 3,4) Since our studies revealed differential effects of chemopreventive agents in our two liver models, 5,6) the possibility arises of different mechanisms underlying endogenous and exogenous hepatocarcinogenesis in rats.…”

Alterations of the M6p/Igf2 receptor gene in hepatocellular carcinomas induced by N‐nitrosodiethylamine and a choline‐deficient L‐amino acid–defined diet in rats

“…With the exogenous agent, the method for the production of HCCs was as previously described [1,2]. Fifteen animals received DEN at a single intraperitoneal (i.p.)…”

“…N ‐nitrosodiethylamine (DEN) is one of the best‐known liver carcinogens in rats. We have reported that a cell‐cycle disturbance induced in DEN‐initiated hepatocytes by colchicine gives a growth advantage to putative preneoplastic lesions under conditions of partial hepatectomy and selection pressure, so that a high incidence of hepatocellular carcinomas (HCCs) can be obtained within a short latent period [1,2]. We have also demonstrated high yields of HCCs associated with cirrhosis caused by chronic administration of a CDAA diet that does not contain any known carcinogens [3].…”

Fhit gene alterations in hepatocarcinogenesis induced by a choline‐deficient L‐amino acid–defined diet in rats

“…N ‐nitrosodiethylamine (DEN) is one of the best‐known liver carcinogens in rats. We have reported that a cell‐cycle disturbance induced in DEN‐initiated hepatocytes by colchicine gives a growth advantage to putative preneoplastic lesions under conditions of partial hepatectomy and selection pressure, so that a high incidence of hepatocellular carcinomas (HCCs) can be obtained within a short latent period [255,266]. We also have shown high yields of HCCs associated with cirrhosis that are caused by long‐term administration of a choline‐deficient L ‐amino acid–defined (CDAA) diet, which does not contain any known carcinogens [27].…”