RADIOSENSITIZATION AND CHEMOSENSITIZATION OF AERATED AND HYPOXIC MAMMALIAN CELLS

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A major portion of this study has dealt with the importance of cellular redox systems such as glutathione (GSH) and related enzymes to the cell's defense against ionizing radiation and chemotherapy drugs. Recent studies have clearly shown that inherent GSH levels do not significantly contribute to the radiation response. Previous work from this laboratory has indicated that inherent GSH levels do have a marked impact on chemotherapy drugs and specific nitroimadazole radiation sensitizers. More recently we have shown that cell lines high intercellular GSH are not sensitized as much as cell lines with a low GSH levels to hypoxic preincubation with misonidazole followed by aerobic exposure to melphalan. These findings are of particular importance since misonidazole is being used clinically as a sensitizer for drugs such as melphalan. Several laboratories have shown that the intercellular levels of GSH in human tumor lines are much higher than rodent cell lines. It has also been shown that high intercellular GSH levels afford resistance to a number of chemotherapy drugs. Our laboratory and others have questioned whether or not human tumor cells in vivo have high intercellular GSH levels. We have now evaluated some 40 biopsies from human lung cancer and have found that the GSH levels in the tumor are not markedly different from GSH levels taken from normal lung. An exception has been identified, namely, squamous lung cancer. Biopsies taken from these tumors indicated a subpopulation of cells with extremely high GSH levels. In order to make these measurements we have spent considerable time working out techniques. A combination of cell disaggregation and staining cells with a GSH specific stain, monochlorobimane, along with HPLC techniques have enabled us to identify subpopulations within tumor cell digest and establish their GSH levels. 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.