OSMOTIC OPENING OF THE BBB TO ANTI-TUMOR AGENTS

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.