Epidemiological evidence has shown that ionizing radiation in man is a carcinogen with a relatively long latency period. Evidence is also emerging to indicate that patients with a history of prior irradiation of benign or malignant lesions are at increased risk of developing subsequent neoplasms. The long latency period could be explained by the initiating potential of ionizing radiation followed by promotion of benign and malignant tumors, and ionizing radiation may have the ability to convert benign tumors to malignant tumors. To date these important questions have not been directly addressed experimentally. Therefore the overall goal of this proposal is to investigate the initiating potential of ionizing radiation in the classical mouse, two-stage model of carcinogenesis and to investigate the activation of the ras family of oncogenes in radiation-induced tumors. The biological questions being asked in this proposal include: 1) Can it be shown that ionizing radiation has initiating potential in mouse skin by studying the ability of the agent 12-0-tetradecanoylphorbol-13-acetate (TPA) to promote skin tumors in mice treated with a single subcarcinogenic dose of ionizing radiation? 2) Can ionizing radiation act to enhance the rate of conversion of benign papillomas to malignant squamous cell carcinomas in MNNG initiated and TPA promoted animals? In parallel molecular studies the following questions would be asked: 1) In ionizing radiation-induced skin tumors, what member of the ras family of oncogenes (Ha-ras, K-ras, N-ras) can be shown to be activated using the NIH/3T3 transfection assay? 2) What specific base mutations are responsible for ras activation? (By isolating, cloning, and then sequencing both the normal and activated ras genes) The activation of Ha-ras has been found in chemically initiated skin tumors, but nothing is known about which ras gene is activated or what mutations are responsible for activation in radiation-initiated tumors. Potential differences in the chemical and radiation-activated ras genes and between chemical versus radiation-induced mutations in the ras genes may help in future studies of human tumors in which investigators may attempt to identify etiological factors.
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