The overall objective of the proposed studies is to develop an improved method for delivering interferon to diseased brain tissue. A mouse glioma has been chosen as a model system since it is responsive to interferon (IFN) treatment and will enable mechanistic issues to be addressed. Under normal conditions, the blood-brain-barrier (BBB) limits the types of therapeutic approaches that can be used to treat not only glioma but also opportunistic infections in the brain. Prior studies in this laboratory have demonstrated that after single intravenous administration IFN is not detectable in normal mouse brain. However, It is detectable in the cerebral hemisphere ipsilateral to BBB disruption when administered following the osmotic alteration of the BBB with intracarotid administration of arabinose. Because of the controversy surrounding the clinical application of osmotic BBB alteration, alternative therapeutic approaches for cerebral glioma will also be evaluated. They will include slow and constant IFN delivery using an osmotic mini pump placed: 1) subcutaneously (sc), 2) intracerebrally (ic), or 3) intravenously (iv) in glioma bearing animals. The results of this approach will be compared to the results obtained after repeated systemic administration of IFN. A reproducible model of cerebrally implanted mouse glioma (G-26 in C57BL/6 mice) has been established in this laboratory. Biological and immunoenzymatic assays will be used to measure levels of IFNs in plasma and in the tumorous brain. IFN effects on tumor progression will be assessed by animal median survival times, glioma cell proliferation, brain macrophage infiltration, major histocompatibility (MHC) class 11 (la) antigen induction, and glioma glycosaminoglycan (GAG) coat synthesis. Brain levels of norepinephhne and plasma levels of ACTH and corticosterone will be assessed due to evidence of bidrectional influences between IFN and the hypothalamic-pituitary-adrenal axis. Although the proposed studies will evaluate more effective ways of treating brain tumors, the protocols may also have utility in treating AIDS related opportunistic infections of the brain. They will also provide a better understanding of how IFN might activate defense mechanisms within the normal and diseased brain.
