RADIOBIOLOGY OF LETHALITY, MUTATION, AND TRANSFORMATION

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Ionizing radiation, sunlight, and chemicals that interact with DNA are generally cytotoxic, mutagenic, and oncogenic. Cell killing, is an essential end effect in the therapy of cancer. The lethal effects of radiation are radiation are also important in mutagenesis and neoplastic transformation because cell viability is required for these endpoints to be expressed. In people, radiation has been established as a mutagenic and oncogenic agent; a number of chemicals, including photosensitizers of cells like the polycyclic aromatic hydrocarbons (PAH's), are recognized to have similar properties. For these reasons, a study of the biological effects of radiation and genotoxic chemicals is relevant both to issues of public health and the treatment of cancer. Each part of this proposal is directed at basic radiobiological and molecular processes in mammalian cells. Still, an underlying them is the roles of repair and cell kinetics in the endpoints above. For example, in mutagenesis, we seek to understand why the yield of mutations decreases with dose rate; if this decrease is accompanied by qualitative shifts in the genotypes that are produced; and what role repair competence plays in such shifts. In connection with chemical agents that may be present in the environment along with radiation, we have determined that one PAH can reduce the effectiveness of another. The implications of this observation will be followed up first because repair-stimulated PAH action is important in its own right, and second because a determination of how radiation and PAH's in the environment interact requires that the action of each should be understood. Lastly, the observation of enhanced sensitivity of G2-/M-phase cells to killing, mutation, and transformation will be vigorously pursued because of the role of mitosis in cancer biology, and because this cell-cycle window of sensitivity leads to important predictions of the effects of low, protracted doses of radiation.