We have been following two lines of research for developing strategies to utilize nitric oxide (NO) in cancer treatment. The first is by the use of NO donor compounds while the second is to control this diatomic radicals cellular production by modulating different cytokines. Recent studies have shown that either NO generated endogenously or from donors can inhibit respiration in cells. This then results in the increase in oxygen availability thus radiosensitizing cells. An additional line of research in developing methods to direct NO to the tumor region has been the development of tamoxifen NO donors. In collaboration with Martin Brechbiel, we have successfully generated two derivatives, one a S-nitrosothiol complex and the other a NONOate complex and are currently characterizing their biological properties. We have been probing different methods which provide the correct NO chemistry from leukocytes and cells transfected with inducible nitric oxide synthase. Our goal is to create cells that produce the correct chemical stress in the local region of the tumors. We have developed a fluorimetric assay which is able to screen various different cells for nitrosative stress. Our chemical donor experiments have suggested that nitrosative stress is the chemical profile most effective in enhancing the chemotherapeutic and radiation sensitization. A variety of murine macrophage cell lines have been examined with different cytokine and lipid polysaccharides. We are working on methods to detect these either by fluorescence microscopy or in vivo with microdialysis. - radiation, nitrosation, oxidative stress,
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