Radiation therapy following surgery is the most effective treatment for malignant brain tumors, but clinically admissible radiation doses are limited because the radiation also damages normal tissue. If that damage could be ameliorated, radiation doses delivered to brain tumors might be increased and therapeutic efficacy enhanced. Radiation-induced brain damage often includes damage to the cerebral vasculature, as evidenced by prominent blood-brain barrier breakdown and cerebral edema. In this study, we wish to elucidate the mechanisms responsible for the sensitivity to radiation of the cells composing the cerebral vascular system. This work could suggest possible therapies directed toward ameliorating the radiation sensitivity of normal brain. We hypothesize that the differing endogenous levels of antioxidants, such as ascorbate, and pro-oxidants, such as the naturally occurring free radical nitric oxide (NO), are responsible for any differential radiosensitivity of cerebrovascular cells: and that modification of endogenous oxidant levels can modulate radiosensitivity. To test this hypothesis, we will examine the radiation sensitivity of primary cultures of cerebral endothelial cells, astrocytes, and pericytes from normal rats and mice and transgenic mice overexpressing human copper-zinc (CuZn)-superoxide dismutase (SOD) in the presence of various antioxidants and pro-oxidants.
Our specific aims are: 1) to quantify the susceptibility of primary cell cultures of rat cerebral endothelial cells, astrocytes, and pericytes to radiation-induced injury; 2) to correlate radiation-induced injury to cerebrovascular cells with levels of antioxidants; 3) to determine whether physiologic stimulation of NO production enhances radiation-induced injury to cerebral endothelial cells, to determine whether blockage of NO can ameliorate such injury, and to establish any role the superoxide anion may have in NO-mediated damage; 4) to elucidate the molecular mechanism by which modification of endogenous antioxidant systems (SOD, catalase, and glutathione peroxidase) or production of NO modulate the degree of radiation-induced cell damage; and, 5) to determine whether the level of radiation-induced injury is altered when cells are grown as mixed cultures (endothelial-pericyte and endothelial-astrocyte), and whether any modification of the response is due to cell-to-cell transfer of antioxidants, to the induction of antioxidant production, or to transfer of free radicals such as NO.
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