Cultured cells of rodent and human origin will be used to evaluate fundamental and practical aspects of the treatment of cancer with densely ionizing radiations, hypoxic cell radiosensitizers and cytotoxic agents used in chemotherapy. Well tried radiobiological systems will be employed to compare the relative biological effectiveness (RBE) and the oxygen enhancement ratio (OER) for the new generation of hospital based neuron generators in the United States, Great Britain and Continental Europe. Further efforts will be made to link RBE with physically measurable microdosimetric quantities. More fundamental radiobiological studies will be performed with the heavy ion beams at the Bevalac and at Darmstadt. Studies with hypoxic cell sensitizers have led to an appreciation of their interaction with various biochemical pathways and the importance of overall cellular redox potential in the response of cells to ionizing radiation. The role of factors that contribute to the cells redox state, such as non-protein and protein sulfhydryls, NADH and NADPH as well as DNA repair will be studied using genetically altered human skin fibroblast lines. These will include cell lines derived from patients with 5-oxoprolinuria (decreased GSH levels), glucose-6-phosphate dehydrogenose (decreased NADPH levels) and xeroderma pigmentosum (decreased excision and long-patch DNA repair). In parallel with these mutant lines, the radiation response will be studied of cells in which non-protein sulfhydryl levels have been manipulated by the use of agents such as Buthionine Sulfoximine (BSO) and Diethyl Maleate (DEM) as well as the nitroimidazole hypoxic cell radiosensitizers, both established and novel. In parallel with the radiation studies, chemosensitization will be investigated. A range of new radiosensitizers, alone or in combination with thiol depleting agents, will be used to enhance the effectiveness of antineoplastic agents.
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