The major hypothesis in this proposal is that a cause of clinically significant heterogeneity in radioresistance between tumors lies in their radiation response modifiers. This hypothesis will be investigated utilizing melanoma and renal cell carcinoma lines. A cause and effect relationship as well as a correlation will be sought between radiation resistance and cytokine expression. One of several investigative approaches will be to genetically manipulate selected human tumor cell lines using retrovirus vectors so that they express specific cytokines and determine whether this changes cellular radioresistance. Mechanisms of radioresistance will be examined within these well-defined tumor cell systems, with initial emphasis on certain free radical scavengers, cell cycle effects, and recovery from potentially lethal radiation damage since there is evidence that these mechanisms are subject to modification by cytokines. The significance of this study on cytokine-directed radioresistance is 3-fold: 1) if it is possible to correlate cytokine profile and/or phenotypic marker expression with radioresistance, then these measures could be used to predict radiation response. 2) Cytokines or cytokine receptors could act as targets and/or vehicles for enhancing radiosensitivity prior to and during radiation therapy, as well as for independent therapeutic attack. 3) Knowing the importance of endogenous cytokines to radioresponsiveness, and the pathways by which they operate, will improve our understanding of the basic radiobiology of cell killing and of the nature of """"""""intrinsic"""""""" tumor radioresistance.
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