The presence of the blood-brain barrier (BBB) prevents most available antitumor agents from effectively penetrating brain tumors. A key factor may be the characteristic steep drug dose- response curve where reductions as small as 20% can result in dramatic loss of efficacy. Extensive animal studies have shown that BBB disruption markedly increases drug delivery to tumor & surrounding brain. Of agents evaluated, only methotrexate (MTX) & cyclophosphamide (CTX) are without significant neurotoxicity. This proposal continues the evaluation of antitumor agent delivery, toxicity & efficacy when administered with osmotic BBB disruption. BBB disruption prior to MTX, CTX & procarbazine treatment in patients with primary & metastatic brain tumors has resulted in significant efficacy particularly with primary CNS lymphoma. Two new antitumor agents will be investigated regarding delivery & efficacy in the nude rat model of intracerebral human tumor xenografts. Preclinical toxicity trials will be done in the dog. Monoclonal antibodies (MAb) specific for human tumor cell antigens will be intensively studied. BBB disruption significantly increases MAb (IgM, IgG & Fab) delivery to brain however, intact IgM tends to nonspecifically bind to brain. Thus, IgG & immunoglobulin fragments appear to have the greatest promise for diagnostic & therapeutic use. IgG, Fab & F(ab')2 fragments of specific & """"""""nonsense"""""""" antibodies will be evaluated in tumor-bearing nude rats. Studies of immunohistology, quantitative auto- radiography & MAb concentration x time will evaluate binding & localization. MAb MG-21 (melanoma specific) & L6, which binds to human lung & breast cancer, have both shown systemic efficacy & thus will be evaluated for cytotoxicity in tumor-bearing rats. Delivery to intracerebral tumor after disruption of a panel of MAbs & efficacy of high specific activity radiolabeled MAb will also be assessed. Systemic drug inactivation with MAb will be investigated on the basis that brain tumors are much less permeable to higher molecular weight agents. Studies will examine the effects various anesthetics have on drug & protein delivery to brain after BBB disruption. The permeability effect of steroid treatment & BBB disruption in intracerebral tumor-bearing rats will also be examined. Our overall objective is to improve delivery to antitumor agents to the brain & brain tumors. This proposal is in response to the program announcement in Surgical Oncology & is a continuation of a surgical CREG.
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