When Mammalian cells are sequentially irradiated with a low-LET radiation (e.g. x-or Gamma-rays) and a high-LET one (e.g. fast neutrons, heavy ions, pi-mesons) cell killing is enhanced to the extent that the effect may be regarded as synergism. The type(s) of the involved damage caused by the low-LET radiation and that caused by the high-LET radiation has not been clearly defined, although they both have been shown to be repairable. The mechanism(s) for the """"""""synergism"""""""" is not known. In this proposal, we consider two working hypotheses: (1) suppression of repair system(s) in mammalian cells is a predominant factor which leads to the synergistic cell killing following mixed high- and low-LET irradiations, and (2) the sublethal damage produced by low-LET radiation, and a known form of potentially lethal damage inflicted by high-LET radiation are the major components of cellular damage responsible for the combined action of cell inactivation. To test hypothesis (1), we will first study the effects of mixed radiation exposures on the kinetics of DNA strand break rejoining and on DNA synthesis in Chinese hamster cells. Second, we will design survival experiments whose results can be analyzed and/or predicted by the Repair-Misrepair model of Tobias et al, and the interaction model of Zaider and Rossi. To test hypothesis (2), we will compare the repair kinetics of the damage involved in combined-radiation experiments to the kinetics of those defined as sublethal damage and tonicity-related potentially lethal damage. These experiments will be conducted with exponential-phase and plateau-phase cells. Irradiations will be performed at a facility which has been designed for simultaneous and sequential treatments of low-and high-LET particles.
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