We have been following two lines of research for developing strategies to utilize NO in cancer treatment. The first is by the use of NO donor compounds while the second is to control its production from the enzyme nitric oxide synthase whose activity is modulated by different cytokines. We have catalogued the effect of various NO donors on sensitizing hypoxic mammalian cells to radiation as well as evaluating the effects of these compounds on the cytotoxicity of different alkylating agents. We discovered that there is a significant difference between NO donors with respect to these modalities of cancer treatment. Chemical donors such as NONOates and nitrosothiols sensitize cells to radiation under hypoxia, however, only NO derived from NONOates sensitize chemotherapeutic drugs such as cisplatin, melphalan, and thiotepa. We have shown that NO from NONOates can inhibit DNA repair proteins such as ligase and this appears to be the mechanism by which cells are sensitized to chemotherapeutic agents. Cytokine stimulation of some cells results in not only NO formation, but also other reactive chemical species such as superoxide (O2-) as well. We have explored the chemistry between NO and O2- which depends on the relative rates of formation of these radicals. Depending on the relative production of either radical, nitrosative and oxidative stress can be modified. We have preliminary results which suggest that the cytotoxicity of different chemotherapeutic agents may depend on either an oxidative or nitrosative pathway. It has been shown that immune cells as well as some cancer cells can be stimulated by cytokines to generate NO as well as other oxidants. We have discovered that NO formation from cytokine stimulated immune cells can be enhanced by radiation adding an important tool to modulating endogenously formed NO. We have begun to explore the effects of cytokine stimulated NO on the cytotoxicity of different antineoplastic agents and radiation. Taken together, we will be able to show NO and other oxidants can be modulated by different components of the immune system.
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