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(PP234) Modifying the radioresponse of neural precursor cells through changes in oxidative stress.
Giedzinski, Erich1, Baure, Jennifer1, Rola, Radoslaw2, Fike, John1, 2, Limoli, Charles*,1, 1 Radiation Oncology, San Francisco, CA2 Neurological Surgery, San Francisco, CA
ABSTRACT- The mammalian forebrain contains multipotent neural precursor cells located within the subgranular zone of the hippocampal dentate gyrus. The progeny of these cells differentiate into neurons (neurogenesis) and may play a role in the repair of the damaged CNS. Irradiation has been shown to deplete the number of hippocampal precursor cells and inhibit neurogenesis; these are associated with the devlopment of cognitive impairement. To understand the factors critical in regulating the response of these cells to irradiation in vivo, we have developed an in vitro model using cultures of primary neural precursor cells isolated from the hippocampus of rats and mice. These models have revealed that neural precursor cells are hypersensitive to changes in redox state, exhibit high levels of endogenous reactive oxygen species (ROS), and show increased ROS from days to weeks after irradiation. Neural precursor cells are sensitive to oxidative stress, and when they are subjected to different oxidizing treatments their sensitivity to ionizing radiation increases. Extended treatment (3-5 days) with hydrogen peroxide (5-20 uM) or glucose oxidase (1-3 mU/ml) leads to modest cell kill, but can increase radiosensitivity 20 - 60% over a dose range of 1-5 Gy. Similarly, cells subjected to metabolic oxidative stress through manipulations of the microenvironment are also sensitized to the action of ionizing radiation. The growth fraction of irradiated cells cultured under high ROS are reduced by as much as 50% compared to controls cultured in the absence of this stress. Lastly, mitochondrial electron transport chain poisons antimycin A or menadione have been used to increase leakage of mitochondrial derived superoxide which can be monitored over time with ROS sensitive dyes. When coupled with efforts to minimize drug toxicity, these agents provide an effective means for controlling the induction and extent of oxidative stress. Strategies using antimycin A and menadione are being developed to determine the extent to which radiosensitivity can be attenuated by timing irradiation to coincide with the relative maximum or minimum of ROS production. Additional data will be presented highlighting how these findings might be used to overcome certain adverse sequelae in the irradiated CNS.
Key words: neurogenesis, oxidative stress, radiosensitivity, redox state
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