Characterization of the molecular controls of cellular responses to DNA damage provides insights into mechanisms of tumor development and improves understanding of determinants of cell survival following anti- neoplastic therapy. Experiments proposed in this application explore the roles of the tumor-related gene products, p53 and c-myc, in controlling radiation-induced cell death and tumor development. Previous studies have demonstrated that the tumor suppressor gene, p53, the most commonly mutated gene in human cancers, is a critical participant in the arrest of cells in the G1 phase of the cell cycle following ionizing irradiation. Utilizing cells in which the status of the p53 gene is known or cells in which the p53 gene has been manipulated, the effect of loss of this G1 checkpoint in genetic instability following exposure to ionizing radiation will be assessed. Genetic instability, which is probably an important variable in tumor development, will be evaluated following irradiation by both standard chromosomal examinations and by the use of selectable vectors and chromosomes in which recombination events and chromosome loss can be quantitated. Based on preliminary data and data in the literature, the role of the dominant oncogene c-myc, commonly translocated or abnormally expressed in tumors, in controlling both the arrest of cells in G2 and apoptotic cell death after irradiation in certain situations will be examined utilizing cells in which c-myc expression and/or function has been altered. The biochemical mechanisms involved in controlling c-myc response to irradiation are a major part of these investigations. Potential interactions between the p53- dependent pathways and a c-myc pathway induced by irradiation in controlling cell cycle perturbations and cell survival will be examined utilizing cells in which neither, one or both of these genes or their functions have been altered. These investigations should provide novel insights into both mechanisms of tumor development and improved ways of utilizing radiation therapies in attempts to selectively kill malignant cells. Thus, new approaches to minimizing radiation-induced tumors and maximizing therapeutic index in the treatment of tumors could result from these studies.
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