White matter necrosis (WMN) constitutes a dose-limiting toxicity of combined radiation and chemotherapy treatment of CNS neoplasms. Unfortunately, the pathophysiology of WMN is not known, hampering prediction, prevention and treatment. This research proposal will test the hypothesis that WMN results from the intramitotic death of glial cells in the cervical spinal cord or glial precursors in the subependymal plate (SEP), caused by chemotherapy (CT), radiotherapy (RT) or a combination of both modalities. This overall hypothesis will be evaluated by testing six specific hypothesis in the juvenile rat: 1) Proliferating cells of the SEP in the 9-day-old rat give rise to cells which migrate to the subcortical white matter. Ablation of these cells results in WMN; 2) Whole brain RT in the juvenile rat results in sequential, dose-dependent alteration in the cell density of the SEP and subsequent dose-dependent white matter change, including WMN; 3) Single bolus administration of MTX or thioTEPA results in dose-dependent alteration of SEP cell density. Serial administration results in persistent, dose-dependent decline in SEP cell density and subsequent dose-dependent white matter change, including WMN; 4) Combined treatment with RT and CT results in an additive loss of cells in the SEP; 5) When administered continuously during the latent period prior to the onset of WMN following cervical cord RT, MTX increases the incidence of WMN; 6) RT of the cervical cord and prolonged intraventricular administration of MTX each results in sequential and dose-dependent depletion of the cervical cord glial cell population. When both are administered, the decrease in glial cell number is additive. These hypotheses will be tested by examining glial or SEP cell depletion and incidence of WMN in animals treated at nine days of age with CT, RT or both modalities. An understanding of the pathophysiology of WMN will allow pre-clinical testing of proposed antineoplastic agents for chronic neurotoxicity, either when used alone or in combination with RT and may allow rational scheduling of antineoplastic treatment to minimize the possibility of this adverse outcome. Finally, radio-chemoprotection might be possible if the target cell population is known.
