Chemotherapy has been relatively ineffective for the treatment of brain tumors, in part because the blood-brain barrier (BBB) and blood-tumor barrier (BTB) limit agent delivery and therefore dose intensity at the tumor. Enhanced chemotherapy dose intensity may be achieved by increasing drug dose or activity, decreasing side effects, and increasing drug delivery to brain tumor with osmotic BBB disruption (BBBD). Two different two-compartment models for enhanced chemotherapy will be tested in a rat intracerebral xenograft model. In the "differential permeability" model, the large brain tumor is relatively permeable compared to surrounding brain, and therapeutic drug levels may be obtained by increasing systemic drug administration. In the "barrier dependent" model in small tumors, the BTB and BBB in the brain around the tumor are relatively impermeable, and circumventing the blood-brain barrier is necessary to achieve therapeutic drug levels. Aim 1 will assess bone marrow protection with thiol agents such as N-acetylcysteine or sodium thiosulfate. We will test whether chemoprotection can be obtained without reducing chemotherapeutic efficacy. In Aim 2 the efficacy of enhanced chemotherapy against rat brain tumors will be evaluated by tumor volumetrics and magnetic resonance imaging. Chemotherapy cytotoxicity will be enhanced by reducing glutathione levels with buthionine sulfoximine, or blocking alkylguanine-DNA alkyltransferase with 06- benzylguanine. Aim 3 will characterize the delivery, toxicity and efficacy of radioimmunotherapy with tumor specific monoclonal antibodies (mAbs), focusing on use of targeting radiation with beta emitters (track length 2-5 mm). We will determine if thiol chemoprotectants can reduce the bone marrow toxicity associated with radioimmunotherapy. Aim 4 will be a clinical trial investigating immunotherapy in recurrent primary central nervous system lymphoma. A phase II study will assess rituximab immunotherapy in combination with aggressive BBBD chemotherapy. We also propose a Phase I study of yttrium-90 labeled anti-CD20 mAb delivered with BBBD to be used after cytoreduction with chemotherapy and rituximab. In summary, we hypothesize that the combination of approaches using both two-compartment models will demonstrate the feasibility of potentiating drug activity against intracerebral tumors while reducing systemic toxicity. This proposal is response to Brain Tumor PRG sponsored by NINDS and NCI.