The major objectives of this project are to identify approaches that will result in radiation enhancement of cell killing both in aerobic and hypoxic conditions and to better understand mechanisms of radiosensitization. Much of our previous work identified intracellular glutathione (GSH) as important in governing the cytotoxicity of certain chemotherapy drugs and hypoxic cell radiation sensitizes. We have recently shown that hypoxic radiation sensitization by two new nitroimidazoles is markedly enhanced with GSH depletion. In collaboration with the Surgery Branch, we have measured GSH levels from a number of lung tumor biopsies and compared than to normal lung GSH. Our findings show that 1) precise GSH measurement of tumor cells are complicated by infiltration of leukocytes (infiltration in some tumors exceeded 40% of the total tumor mass) in lung tumors; 2) normal lung GSH values were remarkably constant among the 27 samples evaluated; 3) Several squamous lung cancer samples had populations of tumor cells in the biopsy with 3-5 fold higher GSH levels than found in normal lung, Such Studies support the idea of using an inhibitor of GSH synthesis to possibly enhance both radiation and chemotherapy cytotoxicity and indeed clinical trials have been initiated at other institutions to test this possibility. Presently we are working with a series of GSH esters that might be used to elevate GSH in cells and tissues with the idea of restoring cells/tissues to normal GSH levels after depletion and drug treatment. Additionally, we have demonstrated that non-lethal hyperthermia administered concurrently with continuous low dose irritation results in dramatic radiosensitization.This will be further explored including GSH depletion. Lastly, we have demonstrated that human B-lineage lymphoid precursor cells radiosensitive.
