Because 6 of 7 brain tumor cell lines studied in our laboratory show an increased sensitivity to BCNU under hypoxic conditions, this appears to be a common, but not universal, trait of brain tumor cells. Moreover, there is one published report showing increased BCNU cytotoxicity in hypoxic KHT-iv cells, but there are also reports showing that BCNU produces equal cytotoxicity in oxic and hypoxic CHO and EMT6 cells. It is not known whether these different findings are due solely to differences specific to individual cell lines, or to the considerable differences in the experimental protocol followed, or to both, but clearly it is incorrect to universally classify BCNU cytotoxicity simply according to oxygenation status of the cells. In brain tumor cells that exhibit increased sensitivity to BCNU under hypoxic conditions, the dependence of this phenomenon on timing is not known, the degree of hypoxia needed for the phenomenon to occur is not known (only radiobiologically hypoxic cells have been studied), and the mechanisms underlying this phenomenon are not known. To further understand the cytotoxic effects of -BCNU under hypoxic conditions, we propose timing and mechanistic studies using 9L rat brain tumor cells and selected human brain tumor cell lines that exhibit varying sensitivity to BCNU. Results of these studies should help identify the determinants underlying the increased cytotoxicity of BCNU in brain tumor cells under hypoxic conditions, and may suggest whether it would be useful to investigate means and parameters for altering oxygen tension in brain tumors (or possibly other solid tumors) in situ for possible applications to clinical treatment with BCNU. Perhaps more likely is that such data would be useful in planning combinations of drugs, each of which might be targeted towards a separate subpopulation of cells, eg oxic and hypoxic, in the tumor. Specifically, we propose to: 1) define the degree of hypoxia and the timing required to produce enhanced BCNU cytotoxicity in exponentially-growing monolayer cultures, and determine whether similar enhancement of BCNU occurs for other selected compounds; 2) investigate whether the enhancement of BCNU cytotoxicity depends on the growth status of the cells (cycling vs noncycling, cell cycle phase, cell-cell contact); and, 3) identify possible mechanisms of the enhancement.
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