RADIOBIOLOGY OF LETHALITY, MUTATION, & TRANSFORMATION

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Radiation, and DNA-active chemicals, are generally cytotoxic, mutagenic, and oncogenic. Cell killing, which is essential in the therapy of cancer, is also important to the assessment of mutation and neoplastic transformation because cellular viability is required for both of these end effects to be expressed. Radiation is recognized as mutagenic and oncogenic in people and a number of the chemicals which are used in cancer therapy have similar properties. It follows, therefore, that the study of the biological effects of radiation and genotoxic chemicals is important both to issues of public health and to the treatment of cancer. This research will focus mainly on ionizing radiation although near-ultraviolet, sunlight-simulating light and certain chemicals will also be studied. A primary theme will be damage and repair processes in mammalian cells in culture as these processes influence lethality, mutagenesis, and neoplastic transformation. The underlying notion, which has applied to the work of the Principal Investigator over the past 30 years, is that the cell and molecular biology of damage and repair are opposite sides of the same coin. That is, progress on one aspect of the problem complements the understanding of the other. A study of mechanisms of damage and repair draws together the otherwise disparate features of the radiobiology of protracted low doses, as they may constitute an environmental hazard, and the radiobiology of single-to-protracted moderate-to-high radiation doses as they may be applied in tumor therapy. In addition, as therapy becomes more effective and lifespans are extended, the likelihood must be faced that second tumors may become expressed. An understanding of the mechanism of tumorigenesis could lead to the development of treatment strategies which minimize such risks. Thus, from another vantage point, this possibility also illustrates an essential coherence of the several parts of the proposed research.