OPENING OF THE BLOOD-BRAIN BARRIER TO ANTITUMOR AGENTS

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In the current proposal, monoclonal antibodies (IgG and F(ab')2) will be combined with BBB disruption to target chemotherapeutic drugs, radionuclides and paramagnetic MRI agents to intracerebral and subcutaneous tumor in nude rats. In these studies, we are combining knowledge obtained during the early years of this R01 proposal with more recent information on antibody delivery and localization to now evaluate therapy, toxicity, and efficacy with antibody targeting. These targeting studies will focus on four delivery systems. First, the L6 antibody conjugated to alkaline phosphatase will be delivered to the LX-1 tumor with BBBD. Subsequently, the administration of phosphorylated chemotherapeutic agents such as mitomycin phosphate will be activated primarily at the site of the tumor by the extracellular alkaline phosphatase covalently linked to the L6 antibody bound to the cell surface. In a second approach, a modulating antibody conjugated to adriamycin will be evaluated. Third, using an effective chelating system that tightly binds radiolabels, localization and efficacy studies will compare gamma- and beta-emitters chelated to the L6 antibody. To date the L6 antibody has been evaluated using either radioiodination or immunohistology. Finally, using the same chelating systems to attach radiolabels to the L6 antibody, paramagnetic substances, such as gadolinium, will be chelated to combine the spatial resolution of MRI with the biologic specificity of localizing monoclonal antibodies such as L6. Associated with these studies will be the neurotoxicity testing of gadolinium contrast agents with vastly differing dissociation constants. The second area to be emphasized in this competitive renewal is the toxicity and efficacy of chemotherapeutic agents administered with and without osmotic BBB disruption before, concomitant with and after external beam radiotherapy. The two least toxic and most efficacious chemotherapeutic combinations in our clinical studies have been methotrexate and cytoxan and more recently the combination of carboplatin and etoposide. The efficacy of these combinations will be evaluated in our nude rat tumor model using the LX-1 human lung carcinoma. In addition, because of past successes in testing the neurotoxicity of chemotherapeutic agents administered with disruption in animals for potential clinical use, we will similarly investigate several new agents. Efficacy will be evaluated not only by survival but also tumor volumetric measurements to assess response both histologically and by serial MRI in vivo scanning. Neurotoxicity testing has a new evaluation dimension in our ability to measure EEG in animals. Our overall objective is to continue to improve delivery of antitumor agents and imaging agents to brain tumors and, finally, to evaluate efficacy of therapeutic approaches. This proposal is in response to the program announcement in surgical oncology and is a continuation of a surgical CREG.