Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine

Abstract

CURRENT understanding of the pathogenesis of neoplasia rests principally on the demonstration^1–3 that the induction of carcinomas of mouse skin by hydrocarbons can be separated into at least two stages. There is evidence of similar stages in the natural history of carcinogenesis of nonepidermal tissues^4–7. For example, Peraino et al.⁶ have shown that short term feeding of acetylaminofluorene to rats followed by a long term diet containing 0.05% phenobarbital results in 100% incidence of hepatomas, whereas animals receiving acetylaminofluorene and no phenobarbital developed 10 times fewer hepatocarcinomas. Peraino's procedure and that of Kitagawa et al.⁷, who fed rats azo dye followed by phenobarbital, required that the carcinogen be fed to the rats for 3–8 weeks. On the other hand, Scherer and Emmelot⁸ have shown that a single large dose of diethylnitrosamine given to rats within 24 h of partial hepatectomy can induce hepatocellular carcinomas, whereas low doses (< 30 mg kg⁻¹), given in the same way, give rise only to small foci of cells deficient in ATPase, comparable with those described earlier^9,10. Further, Solt and Farber¹¹ have reported that a single dose of diethylnitrosamine followed by acetylaminofluorene and partial hepatectomy rapidly produces foci containing γ-glutamyl transpeptidase, in contrast to the situation in normal liver which exhibits no histochemical activity of that enzyme. By combining the procedure of Scherer and Emmelot⁸ with that of Peraino et al.⁶, we have been able to distinguish clearly between two stages in the genesis of liver cancer in rats.