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 class that is activated for the rapid release of NO by glutathione S-transferase and that, by reacting with nucleophilic sulfurs in zinc finger domains of the p7 nucleocapsid protein, shows promising anti-HIV activity in vitro; (ii) development of NO-releasing diazeniumdiolate polymers that, when coated on blood contact surfaces, inhibit platelet adhesion and activation. b) In our studies of NO as a potentially genotoxic agent, we confirmed that two of our NO-releasing diazeniumdiolates are mutagenic in bacteria but found them to be much weaker mutagens in three different mammalian cell assays. We also found no evidence for mutations in immortalized human kidney cells engineered to generate copious quantities of NO. 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 selected 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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