Investigations of the chemistry and pharmacology of nitric oxide (NO) are continuing along three lines. In the drug development area, several potential clinical applications of NO-releasing compounds containing the N(O)NO- functional group are being investigated; for example, their ability to protect mice from the lethal effects of X-irradiation, while at the same time markedly radiosensitizing hypoxic tumors, suggests them to be potentially useful adjuncts to the radiotherapy of cancer. In our basic research program on the interaction of NO with biological macromolecules, two DNA repair enzymes containing critical thiol functions have been shown to be inhibited on aerobic exposure to NO, while NO protected DNA from hydrogen peroxide-induced double strand cleavage. In our studies of NO's genotoxic potential, the mutations produced by bubbles of NO in the supF forward mutagenesis assay (predominantly A:T to G:C transitions) were markedly different from those seen on exposing the plasmid containing the supF gene to either the classical deaminating mutagen, sodium nitrite, or two of the NO-releasing drugs mentioned above (primarily G:C to A:T transitions). Attempts are now underway to identify possible mutations in liver tumors induced in rats by long-term feeding of the important antianginal drug, nitroglycerin, whose clinical utility results from its metabolic conversion to NO.
