In the management of malignant brain tumors, radiation therapy is the single most effective treatment after surgical resection, but the radiation dose that can be used is limited by the tolerance of normal brain tissues surrounding the tumor. Although considerable data are available with respect to the morphologic consequences of irradiation, uncertainty exists regarding its pathogenesis. In the late embryonic forebrain of mammals, the main source of neurons, astrocytes and oligodendrocytes is the subventricular zone, which persists into adulthood as a mitotically active area known as the subependyma (SE). In adults, cells produced in the SE are able to migrate away and, depending upon conditions, can differentiate into neurons, astrocytes and oligodendrocytes, the latter two of which have been shown to be associated with normal tissue radiation response. Cells of the SE may act as a reserve population of undifferentiated cells that could be recruited under particular conditions, such as tissue injury. Further, it has been shown that those cells are very radiation sensitive. It is our hypothesis that the cells of the SE play an important role in the response of normal brain to ionizing irradiation, and that their response can be modified thereby affecting the extent of radiation injury. The following specific aims are defined to test our hypothesis. 1) Deplete normal cells of the SE using a genetically engineered chimeric protein that selectively recognizes the epidermal growth factor (EGF)-receptor, and determine if that depletion enhances the development of tissue injury after ionizing irradiation; 2) Increase the normal cellularity of the SE by intracerebroventricular infusions of EGF and determine if the expanded cellularity changes the development of tissue injury after a subsequent dose of x-rays; 3) Modify the post-irradiation response of SE cells using intracerebroventricular infusions of EGF and determine how such treatment affects cell migration, cell fate, and repopulation of the SE; and 4) Determine if agents that modify cell division or differentiation, can affect the radiation response of SE precursor cells.
