The overall objectives of our research are to determine what role nitric oxide (NO), in combination with oxygen radicals, plays in the etiology of human cancer. There are many inflammatory and pre-cancerous conditions that involve infiltration by phagocytic cells. These cells have long been thought to cause DNA damage by oxygen radicals alone, but recent work in several laboratories suggests a prominent role for NO. as a mutagen and DNA damaging agent. In this Program we will investigate the chemistry and biochemistry of NO. formation from L-arginine, the chemistry of the interaction of the various free radicals generated by phagocytic cells, and the consequences of these radicals for causing DNA damage and mutation. More specifically in the project by Marletta, we will explore the biochemistry of phagocytic cells, particularly neutrophils, for the complex interactions that result from simultaneous generation of both NO. and oxygen radicals. In the Project by Deen the chemistry of these reacting species will be examined to develop reaction- diffusion models which are essential to understand the chemical environment of target cells at varying distances from generator cells. In the Project by Wogon the consequences of DNA damage will be determined by analysis of the mutational spectra generated the same chemical species investigated by Tannenbaum. Each Project will contribute to the creation of a useful paradigm for basic mechanisms of carcinogenesis and potentially new directions in cancer prevention.
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