OXIDATIVE EVENTS IN CANCER THERAPY

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The goals of this Program Project Grant is to advance understanding of the role played by oxidative events in cancer therapy. The influence of peroxidative events on the biology of established tumors and the perturbations induced by treatment will be the focus of all projects. State-of-the-art techniques in lipid analysis, electron paramagnetic resonance (EPR) and antioxidant enzyme transfections will be used. New techniques for detecting lipid-derived free radicals and hydrocarbon generation from tissue culture cells will be paralleled by established measures of peroxidation. A model of fatty acid modification developed by participants provides a powerful tool for tissue culture and dietary studies. Four projects, each directed by established investigators in three departments, provide and integrated approach to the objectives. Project 1 will examine the role of oxidation and especially free radicals in chemotherapy with membrane-directed vs DNA-directed drugs. Initial studies in tissue culture will be carried through to experimental therapeutics in small animals. In Project 2 the importance of antioxidant enzymes to therapy will be explored. Modulation of the enzymes using transfected cell lines, role of oxygen radicals, effect of lipid modification and correlation with peroxidation will be encompassed. Project 3 will investigate ways to enhance efficacy of photodynamic therapy of cancer using membrane-associated photosensitizers that generate singlet oxygen. The role of pro-oxidants, antioxidants and double bonds will be examined. Project 4 is based on the hypothesis that the oxidized fatty acid products formed as a result of lipid peroxidation contribute to the cytotoxic effect of certain anticancer therapies. The overall objectives are to identify more-stable lipid peroxidation products formed in intact neoplastic cells exposed to oxidative stress and investigate how neoplastic cells respond to them. The interaction of the four projects is extensive. Chemotherapy and photodynamic therapy will be included. The EPR Core A will provide state-of-the-art expertise for measurement of free radical generation and will attempt to develop new techniques for the application of EPR to biologic systems. Core B will provide lipid analysis techniques for all projects. Core C will determine antioxidant enzyme protein, mRNA and gene copy as well as transfect antioxidant enzyme sense and antisence cDNAs into various cell lines. In summary, this Program will take advantage of the natural interactions of the investigators in four related projects, each utilizing four scientific cores, to solve an important and underinvestigated aspect of cancer experimental therapies.