Proliferation of preneoplastic lesions after discontinuation of chronic DEN feeding in the development of hepatomas in rat.

Diethylnitrosamine (DEN, 10 mg/kg/day) was fed to rats for 2, 4 and 6 weeks. At different times after feeding with DEN was stopped, growth of preneoplastic lesions has been correlated with pathological evolution (preneoplastic foci, neoplastic nodules and hepatomas). The proliferating fraction in the foci, the cell content, and relative volume of foci increase as a function of the duration of the treatment. The proliferating fraction increases evenly throughout the liver, but, in all experimental modalities, preneoplastic cells show a proliferative advantage over the phenotypically normal tissue. In each experimental group, the proliferative rate correlates with the pathological evolution. After 2 weeks of DEN feeding the growth activity of foci remains very low, and neoplastic nodules are not detectable until the median time of death (14 months). After 4 and 6 weeks, a critical size of the foci is reached, corresponding to the neoplastic transformation, and an increased labelling index is triggered in the lesions and in the phenotypically normal tissue. It is speculated that the "growth pressure" induced by the first carcinogen treatment, associated with the subsequent disturbance of the mitotic control regulation, may be implicated in the process of malignant transformation of preneoplastic lesions.