CELL-PROLIFERATION IN N-NITROSODIETHYLAMINE (DEN)-TREATED RAT-LIVER PARENCHYMA CORRELATED WITH TUMOR-DEVELOPMENT

Background/Aims: The authors wanted to clarify the relationship betwee n the cell proliferation of the liver parenchyma and the development o f hepatocellular carcinoma. Materials and Methods: Liver specimens of 22 N-nitrosodiethylamine-treated rats and 15 normal control rats were examined using laparotomic biopsies at 30 day intervals, followed by t otal liver resections after sacrifice, Magnetic resonance imaging was performed to evaluate the development of hepatocellular carcinoma at e ach period before biopsy. Cell proliferation teas determined using the thymidine analogue, bromodeoxyuridine, which is taken up by S-phase c ells during DNA synthesis. Results: The cell proliferation of the live r 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, e ither 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 herd 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 car cinomas. Moderately or poorly differentiated hepatocellular carcinomas developed at the 120th day. Conclusions: The cell proliferation of no n-cancerous portion of nitrosodiethylamine-treated-rats livers increas ed immediately before the development of hepatocellular carcinomas. De tection 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.