N-Nitrosobis(2-oxopropyl)amine (BOP), at a dose of 10 mg/kg, has induced only pancreatic ductular adenocarcinoma (PDA) in hamsters. BOP methylated liver and pancreas DNA and also 2- hydroxypropylated liver DNA. In this proposal, we will compare the roles of methylation and 2-hydroxypropylation in BOP-induced mutagenicity in V79 cells and by analogy, BOP-induced carcinogenicity. This will be done by using two direct-acting compounds, which each mimic one of the alkylating species generated by BOP Ethyl-N-nitroso(2-oxopropyl)amine (NOPC) (a methylating agent) and the 2-hydroxypropyl analog (NHPC) (a 2- hydroxypropylating agent). Their mutagenicity in the V79 assay will be measured and compared with the alkylation of V79 DNA, which each produces. In both studies, a range of doses will be used. This work could indicate whether alkylation at the 0-4 position of thymine or the 0-6 position of guanine is the crucial site for BOP carcinogenicity. The major aim of this phase of the study is to compare, and it is hoped, to determine the relative roles of methylation and 2-hydroxypropylation in BOP carcinogenesis. Because of the excellent correlation between BOP carcinogenicity and its mutagenicity in the V79 assay, mutagenicity will be used in lieu of carcinogenicity in this study. The second phase is to determine the target cells BOP in the pancreas, using isolated pancreas acinar and duct cells. Their ability to activate BOP to mutagenic metabolites will be measured when the cells are co-cultivated with the V79 cells. The persistence of alkylation, particularly of 0-4-thymine and 0- 6-guanine will be measured in two circumstances. In the first, the pancreas cells will be incubated with BOP, NOPC and NHPC in vitro. The extent and persistence of alkylation will be measured in cultured cells. In the second, the alkylation of pancreas cell DNA will be measured in hamsters given BOP in vivo.
| Lawson, T; Gannett, P (1993) DNA alkylation and mutagenicity of related hydroxypropylating and methylating agents in V79 cells. Teratog Carcinog Mutagen 13:269-75 |
| Lawson, T; Kolar, C (1992) Mutation of V79 cells by N-dialkylnitrosamines after activation by hamster pancreas duct cells. Mutat Res 272:139-44 |
| Lawson, T A (1991) Involvement of lauric acid hydroxylase in the activation of beta-substituted nitrosamines. Cancer Lett 59:177-82 |
| Lawson, T; Nagel, D; Rogers, D (1991) The activation of beta-substituted nitrosamines that are carcinogenic to the pancreas. Int J Pancreatol 10:9-21 |
| Lawson, T; Kolar, C; Nagel, D (1990) The mutation of V79 cells by N-nitrosobis(2-oxopropyl)amine activated by pancreas acinar and duct tissue from Syrian hamsters and MRC-Wistar rats. Mutat Res 240:237-40 |
