MOLECULAR BASIS FOR CNS LATE EFFECTS FOLLOWING RADIATION TREATMENT

University Of Rochester, Rochester NY

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Abstract

Description: (Applicant's Description) Most malignant brain tumors are poorly managed with radiation therapy and the high doses necessary to ablate tumor cells inevitably destroy normal brain cells leading to high morbidity and mortality. In contrast, some of the same tumors in non-nervous tissue respond very well to radiation and/or chemotherapeutic intervention. Moreover, there is an unexpected toxicity of multimodal treatment. Seemingly safe tolerance doses of a single modality of radiation, chemotherapy, or a cytokine lead to enhanced reactions in normal tissues when combined with a second modality, either sequentially or concurrently. Apparently, one modality can sensitize the normal tissue to the next, even when administration is separated temporally by weeks or months. Due to the increased use of combined modalities in aggressively attacking advanced and disseminated malignancies, the search intensifies to overcome tumor resistance, and to limit the toxicity to normal tissues and preserve vital organs. The initial gamma radiation insult to the brain induces proinflammatory cytokines and begins the cytokine cascade which may become amplified upon subsequent irradiation or chemotherapeutic intervention. It is their central hypothesis that initial treatment of the brain with radiation results in a proinflammatory cytokine cascade that sensitizes the brain and results in an increase in normal tissue damage. This hypothesis will be tested in vivo and in vitro by addressing seven specific aims. The first three specific aims will characterize the glial and endothelial cell responses to gamma irradiation both in vivo and in vitro, while the remaining specific aims will examine three possible mechanisms by which the cytokine cascade may sensitize the brain following irradiation.