OPENING OF THE BLOOD-BRAIN BARRIER TO ANTITUMOR AGENTS

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Therapy for brain tumors is complicated by the presence of the blood-brain barrier (BBB), which impedes delivery of chemotherapeutic agents to the central nervous system (CNS). Osmotic BBB disruption (BBBD) is a method to deliver agents through brain and intracerebral tumor. In this proposal, the LX- 1 human small cell lung carcinoma xenograft model in nude rats will be used to examine issues in delivery of antitumor agents to brain tumors and to evaluate the efficacy of therapeutic approaches. The goal of specific aim 1 is to determine why BBD is less consistent in tumor-bearing rat brain then in normal rat brain. We will assess the impact of pharmacologic and physiologic parameters on BBBD in intracerebral tumor-bearing nude rats. This aim is designed to obtain a consistently high percentage of BBBD in experimental animals, will also delineate factors that might be altered in patient BBBD procedures. In specific aim 2 we will investigate the impact of route of chemotherapy administration on therapeutic efficacy. During the past funding period we found intracarotid administration is important for increased drug delivery, but intraarterial delivery in combination with BBBD maximizes drug delivery to tumor-infiltrated areas of brain around the tumor. We will test whether this increased drug delivery is associated with increased anti-tumor efficacy in the nude rat intracerebral tumor model. Specific Aim 3 is to test the effects of sequencing of radiotherapy and BBBD chemotherapy on anti-tumor efficacy in the nude rat model. Their previous studies in normal rats showed that radiation prior to chemotherapy decreased drug delivery to the CNS and increased neurotoxicity compared to the reverse sequence of BBBD chemotherapy prior to radiotherapy. They will test the hypothesis that initial radiotherapy then chemotherapy will also have reduced efficacy. Altogether, the proposed studies are designed to add to our positive record of patient oriented research. Clinical trials, based on previous BBB program preclinical results, have demonstrated that a complete and durable response can be attained in patients with malignant brain tumors, without radiation and without cognitive loss, when delivery is maximized with BBBD. This revised competitive renewal is the continuation of a surgical CREG.