The major focus of these studies is to identify metabolic factors that are involved in cell transformation and progression to neoplasia. These research goals involve use of both in vivo and in vitro systems and employ both genotoxic and nongenotoxic compounds. Some of the biological endpoints which are currently being investigated include DNA damage and repair, cytotoxicity, cell turnover, gene expression and the activation of proto- oncogenes in chemical-induced rodent tumors. Results from studies with the nitrosamines 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1- butanone (NNK) and N-nitrosodimethylamine (NDMA) indicate that mouse lung tumors induced by these nitrosamines contain a K-rat oncogene which had been activated primarily by a GGT to GAT mutation in the 12th codon. This GC to AT transition is consistent with the activation of both nitrosamines by formation of the 06- methylguanine adduct (O6MG). The potential for using DNA adducts as an index of carcinogenic potential is being evaluated in a dose response carcino-genicity study with NNK in the Fischer rat which will examine the relationship between DNA methylation and tumor induction in target cells over a dose range compassing 3 orders of magnitude. The further importance of the 06MG adduct as carcinogenic lesion was demonstrated in studies which evaluated the repair of his adduct in lung cells. The Clara cell, which was found in previous studies to accumulate high concentrations of the 06MG adduct, appears virtually deficient in the ability to remove this adduct, another factor which may contribute to cell initiation by alkylating agents in the lung. The genotoxic potential of methylene chloride, which is weakly mutagenic, but induces lung and liver tumors at non cytotoxic doses in the mouse was evaluated. Studies indicate that this compound may alter the conformation of the DNA; however at present, stable covalent binding to the DNA has not been demonstrated. Factors involved in promotion and progression to the neoplastic state are also being evaluated by examining the effect of cute and chronic exposure to carcinogens on cell proliferation and gene expression.
