Cell proliferation in N-nitrosodiethylamine (DEN)-treated rat liver parenchyma correlated with tumor development

The authors wanted to clarify the relationship between the cell proliferation of the liver parenchyma and the development of hepatocellular carcinoma.

Liver specimens of 22 N-nitrosodiethylamine-treated rats and 15 normal control rats were examined using laparotomic biopsies at 30 day intervals, followed by total liver resections after sacrifice. Magnetic resonance imaging was performed to evaluate the development of hepatocellular carcinoma at each period before biopsy. Cell proliferation was determined using the thymidine analogue, bromodeoxyuridine, which is taken up by S-phase cells during DNA synthesis.

The cell proliferation of the liver parenchyma gradually increased by the 60th day after the initiation of nitrosodiethylamine administration. The labeling index on the 60th day was 0.33 +/- 0.10%. No abnormal mass lesions were identified in either the control rats or the nitrosodiethylamine-treated-rats within this period. By the 90th day in the nitrosodiethylamine-treated-rats, the labeling index of non-cancerous portion had rapidly increased by as much as 1.60 +/- 0.38%, and magnetic resonance imaging demonstrated small high signal intensity nodules on T1-weighted images. They were either hyperplastic nodules or well-differentiated hepato-cellular carcinomas. Moderately or poorly differentiated hepatocellular carcinomas developed at the 120th day.

The cell proliferation of non-cancerous portion of nitrosodiethylamine-treated-rats livers increased immediately before the development of hepatocellular carcinomas. Detection of this rapid increase of cell proliferation in non-cancerous portions of the liver may suggest a high probability of development of hepatocellular carcinoma in the near future.