Enhancement of N-nitrosodiethylamine-initiated hepatocarcinogenesis caused by a colchicine-induced cell cycle disturbance in partially hepatectomized rats.

Abstract

The effects of a colchicine-induced M-phase block of regeneration after partial hepatectomy on early-stage liver carcinogenesis were studied in rats. When administered 1 or 3 days after N-diethylnitrosamine initiation and partial hepatectomy, colchicine increased the mitotic index of regenerating hepatocytes at days 4-6 without evidence of liver cell necrosis. When the protocol was combined with a selection procedure (E. Cayama et al., Nature (Lond.), 275: 60-62, 1978), a significant increase in the size but not number of gamma-glutamyltranspeptidase-positive foci at week 5 was observed in a colchicine dose-dependent manner. This was associated with an elevated incorporation of 5-bromo-2-deoxyuridine into the gamma-glutamyltranspeptidase-positive cells. In a longer-term experiment, the numbers, sizes, and 5-bromo-2-deoxyuridine labeling index of persistent nodules were increased significantly in colchicine-treated rats at week 9. This was associated with significant increases in the incidences and numbers of hepatocellular carcinomas at week 42. The above results raise the interesting possibility that a cell cycle disturbance in the early stage of liver carcinogenesis provides a persisting growth advantage for initiated cells, resulting in enhanced growth of foci and persistent nodules that evolve into hepatocellular carcinomas.