The presence of the blood-brain barrier (BBB) prevents most available anti-tumor agents (chemotherapeutic agents, antibodies) from effectively penetrating brain tumors. The present proposal is designed to continue evaluation of chemotherapeutic agent toxicity and efficacy and to begin evaluation of delivery of antibodies across the blood-brain barrier after BBB modification. In our previous studies, following BBB modification, we have shown that drug delivery of methotrexate, adriamycin, bleomycin, 5-fluorouracil and meglumine iothalamate as well as delivery of an enzyme (hexosaminidase-A) is remarkably increased. We have also shown that osmotic BBB opening increases the permeability (PA) coefficient for methotrexate and 5-Fluorouracil 5-7 times. The proposed animal studies will continue to evaluate drug delivery and efficacy in an animal model of human small cell lung cancer grown subcutaneously and intracerebrally in the nude rat. These studies will evaluate methotrexate efficacy using methotrexate sensitive and resistant human small cell tumors, with and without barrier modification. The studies of neurotoxicity previously performed in the canine will be extended to primates using bleomycin, 5-fluorouracil and cis-platinum administered in association with BBB modification. We will continue studies of methods to maximize the degree of BBB modification and improve methods to monitor BBB opening. This will be accomplished through evaluation of a new contrast agent, effects of pCO2 and blood pressure, intracranial pressure changes and the use of an arterial anti-spasmodic agent. The recent development of monoclonal antibodies specific for tumor cell surface antigens, has made the problem of delivery of proteins across the BBB almost as important as drug delivery. Evaluation of the role that BBB modification may play in the delivery of monoclonal tumor specific antibodies to human tumors is planned by growing human small cell lung tumors subcutaneously and in the brain of the nude rat. Localization of these antibodies to the subcutaneous and intracerebral tumors will then be examined in the presence and absence of osmotic BBB modification. Our overall objective then is to explore ways to improve delivery of anti-tumor agents to the brain and brain tumors. Parenthetically, this proposal is in response to the program announcement in surgical oncology and is a resubmitted, continuation of a surgical CREG.
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