A growing body of epidemiological data suggests that chronic inflammation and infection induce malignant cell transformations and thus play a critical role in the etiology of human cancers. The overproduction of radicals (carbonate, nitrogen dioxide, superoxide radicals) in response to chronic infection and cellular inflammation is accompanied by the reactions of these radicals with polyunsaturated fatty acids (PUFA) in lipid membranes that generate highly reactive, genotoxic oxyl intermediates (peroxyl and alkoxyl radicals). In turn, these radicals contribute to oxidative DNA damage that contributes to the etiology of cancer by poorly defined pathways. Guanine is the most easily oxidizable nucleic acid base in DNA and is therefore a primary target of attack of reactive radical species. The guanine radicals formed undergo a cascade of reactions that culminate in the formation of stable and unstable, genotoxic chemical end-products. However, the reaction pathways, particularly the mechanisms of reaction of peroxyl and alkoxyl radicals with DNA are poorly understood. We have developed new approaches for studying in real time the reactions of unstable nucleobase radicals in DNA with reactive intermediates such as the peroxyl and alkoxyl radicals derived from lipid peroxidation, in aqueous solutions. The analysis of intermediate and final reaction products by a complex of analytical methods including HPLC, MALDI-TOF/MS, and HPLC-ESI-MS/MS, will provide insights into the mechanism of DNA reaction and oxidation pathways.
In specific Aim 1, the mechanisms of radical-radical reactions of PUFA peroxyl radicals and guanine radicals in DNA will be investigated.
In specific Aim 2, the further oxidation initiated by PUFA peroxyl radicals of 8-oxoguanine, a ubiquitous and well known form of cellular oxidative DNA damage, will be assessed.
In specific Aim 3, the detailed mechanisms of the still poorly understood oxidation pathways of PUFA molecules with reactive oxygen species (carbonate radical anion, nitrogen dioxide, superoxide radicals) will be investigated. The development of a variety of cancers including hepatocellular carcinoma, prostate cancer, pancreatic cancer, renal cell carcinoma, and colon cancer, have been correlated with chronic inflammation and infection. A better understanding of the oxidative lipid peroxidation pathways of DNA damage should provide a rational basis for the development of new strategies for the prevention and/or progression of these types of malignancies. ? ? ?
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