The principal objective of this proposal is to gain a better understanding of factors governing cellular responses to ionizing radiation as they bear on dose rate and dose fractionation effects of interest for radiation oncology and issues of low level radiation hazards to humans. Repair processes, the intrinsic sensitivity of cells, and their proliferative status are factors which would be studied. Because confluent cultures nontransformed cells and their transformed counter parts display certain characteristics akin to cell populations in at least some normal tissues and tumors, respectively, we plan to examine and compare responses in such systems, particularly C3H10T1/2 cells, with respect to relationships among radiation dose, dose-rate, dose fractionation, the kinetics of cell turnover, and the repair of potentially lethal damage. The significance of these studies bears directly on currently debated views concerning the cellular basis underlying differences in isoeffect curves of dose-per-fraction vs. total dose for late and early responding (tumor?) tissues. This, in turn, would directly address the issue of whether there is a biological basis at the cellular level to support the notion that hyperfractionation or accelerated fractionation might have clinical advantages over standard fractionation in the treatment of cancer patients. Another portion of this study involves the isolation and characterization of x-ray sensitive and thermotolerantless mammalian cell mutants. The comparative responses of such mutants and their wild-type counterparts would allow identification of defects present in mutant cells and, thus, factors which control these responses in wild-type cells. Repair and cell cycle dependent responses would be studied in x-ray sensitive mutants. In thermotolerantless mutants the development of heat-shock proteins (or lack thereof) would be examined. Thermotolerance is, potentially, an important factor in cancer treatment by hyperthermia, either alone or in combination with drugs or radiation.
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