RADIOSENSITIZATION AND CHEMOSENSITIZATION OF AERATED AND HYPOXIC MAMMALIAN CELLS

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Studies from our laboratory and others have identified the intracellular thiol, glutathione (GSH) as being important in the cytotoxicity of certain chemotherapy drugs and hypoxic cell radiation sensitizers. This finding prompted the question as to whether GSH levels are elevated in human tumors and if so could this explain resistance so often encountered in clinical cancer treatment. In collaboration with the Surgery Branch, we have measured GSH levels from 27 lung tumor biopsies and compared them 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 mass) in lung tumors; 2) normal lung GSH values were remarkedly constant among the 27 samples evaluated; 3) several squamaous lung cancer samples had populations of tumor cells in the biopsy with 3-5 fold higher GSH levels than found in normal lung. The techniques we have worked out should aid researchers who wish to measure GSH levels in tumors. In particular, we have shown that a GSH specific stain, monochlorobimane, along with HPLC techniques will enable identification of subpopulations within tumor cell digests and establish their GSH levels. We have demonstrated basic differences in GSH transferases exist between human and rodent tumors which greatly modify the effectiveness monochlorobimane staining. These approaches and techniques should prove useful in clinical trials where agents such as buthionine sulfoximine are being used to deplete tumor cell GSH. These techniques should enable accurate assessment of tumor cell populations from patients.