MODIFICATION OF RADIOSENSITIVITY BY ALTERATION OF ACTIVITY OF RECEPTOR TYROSINE KINASE AND ITS SIGNAL TRANSDUCTION PATHWAYS

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The purpose of this study is to clarify the role of activation of receptor tyrosine kinase and its signal transduction pathways in determining radiosensitivity and enhancement of radiosensitivity. We have already reported that inverse relationship between EGFR expression and radiocurability in murine tumors, and the underline mechanism is in part attributed to activation of signal transduction pathways by radiation. In addition, we focused on "survival signal transduction pathways" that is consisted of Raf-MEK-p42/p44 ERK and PI3K-AKT/PKB, and a part of the results has already been reported. (1) Radiation activated survival signal transduction pathways, (2) Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity by inhibition of radiation-induced activation of survival signal transduction, (3) Selective inhibition of PI3K or p42/p44 ERK enhanced radiosensitivity, (4) Apoptosis induction may be involved in enhancement of radiosensitivity especially in the cell lines with wild type p53. These results indicated that survival signal transduction pathways plays an important role in determining radiosensitivity, and would be a molecular-target in improving treatment efficacy in radioresistant tumors.