Several chemical topics of current and timely interest in cancer research have been initiated, explored, or completed during this reporting period, that integrate with other LCC projects and efforts. The role of Fenton chemistry in the conversion of nitrosamines, an important class of environmental carcinogens, to their ultimately carcinogenic forms has been explored mechanistically during this reporting period, allowing an assessment of the relative contributions of hydroxyl radical, metal-oxo, and metal-peroxio, species to the overall stoichiometry. In a novel investigation of nitrosamine carcinogenesis, plans and preliminary trials have been made to test the hypothesis that enough nitric oxide is produced by the murine immune system in response to Helicobacter infection to support production of carcinogenic N-nitroso compounds in vivo. This effort is part of the Laboratory's investigation of the mechanism by which this newly-discovered bacterium causes liver cancer. It also complements studies being carried out in this Section on NO-donor drugs as therapeutic agents since potential harmful side-effects must be considered. A study of the structure-activity relationships for the induction of specific cytochrome P450 (CYP) subfamilies (especially CYP2B and CYP1A), as related to tumor promotion, has been brought to successful completion. The data for these and similar studies with barbiturate and hydantoin drug congeners have led to a basis for predicting the activity of untested compounds. For example, we have predicted and shown that the drug, phenytoin, previously thought to be inactive as a liver tumor promoter, is an effective promoter of nitrosamine-initiated liver tumorigenesis in the rat at doses causing maximal CYP2B activity. Our results provide further evidence for a relatively strong association between CYP2B induction in rats and promotion of neoplasia in liver and thyroid. In the coming year much of this project's resource base will be concentrated on Helicobacter- and other tumor development-related aspects. In addition, we will respond to new special opportunities and experimental needs of a chemical nature, as these arise.
