Foci of altered liver cells induced by a single dose of diethylnitrosamine and partial hepatectomy: their contribution to hepatocarcinogenesis in the rat.

Previous findings showed that a single dose of 10–20 mg diethylnitrosamine/kg rat induced foci of atypical liver cells (islands) which might qualify as tumor cell precursors since they closely resembled the preneoplastic lesions resulting from the repeated application of other liver carcinogens. The number of these islands was increased substantially by prior two-thirds hepatectomy, whereas number of cells per island increased autonomously with time.Since partial hepatectomy followed 24 hr later by 20 mg diethylnitrosamine/kg (“priming treatment”) did not produce liver carcinoma, the contribution of this treatment to the carcinogenic process was investigated in the present study. To this end, the amounts of DENA required to arrive at liver carcinoma following daily administration of relatively non-toxic doses of the carcinogen (2·4 mg/kg) started at various times after the priming treatment, were measured. It was found that the contribution of the initial 20 mg/kg dose of diethylnitrosamine to the carcinogenic process was enhanced significantly by prior partial hepatectomy as well as by the time elapsed between the priming treatment and the subsequent instalment of 2·4 mg diethylnitrosamine/kg·day. The positive correlation between the amount of island tissue induced by 20 mg diethylnitrosamine/kg and the latter's contribution to the carcinogenic process furnishes further support for the view that the island cells induced by single application of diethylnitrosamine represent a causal stage in the hepatocarcinogenic process. More generally the present observations bear on the “memory effect” and the “time effect” in chemical carcinogenesis.