Free radical intermediates have been found in the metabolic pathways of a wide variety of organic compounds including antitumor agents which contain a quinone group. Drug activity as well as toxic effects appear to be the result of the purely chemical reactions that these free radicals can undergo. Our working hypothesis is that free radicals from quinone containing antitumor agents are implicated in the agent's activity. Before free radical metabolism can be implicated in a given agent's activity and/or toxicity, it is important that the chemistry of the free radical be known, and that the free radical be found in the metabolic pathway or generated by cells in culture. We plan to continue to investigate the relationship of drug free radicals to drug activity. We found that the free radical generated by electrochemical reduction of diaziquone (AZQ) is the same as that generated by cancer cells in culture. We were able to characterize the free radical in terms of electron spin resonance parameters, electrochemical reduction potentials and light spectroscopy. These results put us now in a position to study the chemical reactions of the AZQ free radical in the test tube and be able to make biologically significant statements regarding the free radical's behavior in vivo. For instance, we are going to look at chemical reactions of the free radicals of AZQ with nucleophiles of biological interest such as GSH and also with DNA. We want to relate their reaction rates to drug activity. We will also study the products of these reactions as possible metabolites. We and others have shown that for AZQ, borohydride reduction elicits DNA strand breaks which cannot be found in the absence of reducing conditions. We want to extend these experiments to in vitro and in vivo conditions where the effect of reduced AZQ against murine leukemia P388 will be investigated. We were able to show that AZQ can be activated by visible light (500 nm). We are now ready to study the photoenhancement of AZQ activity by visible light against cells in culture.
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