Nitric oxide (NO) is a potent and multifaceted bioregulatory agent. This project is aimed at a) finding ways to target NO to specific sites in the body for important research and/or therapeutic applications and b) characterizing the possible role of NO as a determinant of cancer risk. a) Advances resulting from our continuing effort to solve important research and clinical problems by exploiting our accumulating knowledge of the chemistry of the NO-releasing diazeniumdiolates (compounds containing the [N(O)NO] functional group) include: (i) design of a diazeniumdiolate prodrug that on systemic administration is selectively metabolized to NO in the liver, protecting that organ from the toxic effects of tumor necrosis factor-alpha; (ii) introduction of a diazeniumdiolate that releases NO with a 2-second half-life at physiological pH that on intravenous infusion dilates the pulmonary vasculature without detectable systemic effects, suggesting its use to test the hypothesis that NO delivered selectively to the lung will reduce the risk of metastatic tumor development in that organ; (iii) development of NO-releasing diazeniumdiolate polymers for research on the possible involvement of NO in the mechanism of carcinogenesis by implanted foreign bodies (solid state carcinogenesis). b) In our studies of NO as a potentially genotoxic agent, E. coli that was transformed with DNA treated in vitro with an NO-releasing diazeniumdiolate at a concentration of only 1 muM showed markedly increased mutation frequency, but DNA damage could not be detected in cultured human cells treated with the same compound at a 4000-fold higher concentration. We conclude that NO has inherent DNA-damaging potential but that cellular defenses have evolved to protect the mammalian genome from the possible deleterious effects of this critical bioregulatory agent. We will place particular emphasis during the coming year on designing additional drugs and devices capable of targeting NO release to select tissues for use as research tools and for possible therapeutic benefit. At the same time, we will continue to characterize NO's potential activity as a pro- or anticarcinogen.
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