The pathogenesis of liver tumors was studied in rats and mice. The C3H strain of mice has a high spontaneous liver tumor incidence. A very low rate of ras oncogene activation was found in these tumors after NIH 3T3 cell focus assay, PCR amplification and dot blot analysis (cf. project Z01CPO5399). A model was developed in C3H mice to study the role of tumor promoters on cell proliferation in initiated hepatocytes and preneoplastic foci. We have found for the first time that tumor promoters may act by two distinct mechanisms, targeting initiated cells or focus cells for induced mitogenesis and cell growth. We found that aging hepatocytes of these mice were markedly susceptible to the """"""""carcinogenic"""""""" effects of phenobarbital. A similar model system was developed in aging F344/NCr rats with the more important finding that spontaneouslyinitiated cells in the rat liver appeared to possess the GSTP-reactive phenotype. The phenotype of the spontaneously-initiated cells in mice is not known. A similar model for renal tumor promotion after induced initiation has also been developed. We also found that rat renal tumor promoters specifically inhibited gap junctional communication of rat renal epithelium in vitro. The role of cell proliferation on spontaneously-initiated or chemically-initiated hepatocytes is under investigation. The bromodeoxyuridine (BrdU) immunohistochemical technique was further developed by using chronic administration in osmotic mini-pumps or slow-releasing pellets. We found that BrdU, itself, has inhibiting and promoting effects on normal or induced cell proliferation in specific target cells.
