We will evaluate the hypothesis that greater antitumor effects can be achieved by appropriately sequencing selected drugs with radiation treatments. The V79 multicell spheroid tumor model is our choice for these studies, since it presents many of the same """"""""drug delivery"""""""" problems of solid tumors, spontaneously develops both non-cycling and hypoxic cell populations, yet grows in an environment that can be precisely controlled and reproduced. We will define effective drugs as those capable of diffusing into the spheroid, and inactivating cells in that tumor-like environment. This will be determined by our recently-developed techniques of fluorescence-activated cell sorting to selectively recover cells from any desired depth of the spheroids; the sorted cells can be assayed for clonogenicity to determine the activity of the drugs, and whether they interact with radiation. We will further determine whether such interaction(s) are cell cycle or oxygen related, and attempt to exploit them in multifraction exposures. We also intend to evaluate whether flow cytometry techniques for monitoring several indicators of cell function following treatment (eg, cell cycle redistribution, mitochondrial function, DNA synthesis rate, or thiol content) can suggest optimum timing for subsequent treatment in multifraction regimens, and perhaps predict the eventual outcome. We anticipate that our results will identify relevant therapeutic regimens, provide insight into basic mechanisms of drug-radiation interactions, and potentially lead to prognostic tests which may prove valuable during human tumor therapy.
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