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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031770-10
Application #
3169864
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-02-01
Project End
1992-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Muldoon, Leslie L; Neuwelt, Edward A (2003) BR96-DOX immunoconjugate targeting of chemotherapy in brain tumor models. J Neurooncol 65:49-62
Varallyay, Peter; Nesbit, Gary; Muldoon, Leslie L et al. (2002) Comparison of two superparamagnetic viral-sized iron oxide particles ferumoxides and ferumoxtran-10 with a gadolinium chelate in imaging intracranial tumors. AJNR Am J Neuroradiol 23:510-9
Kraemer, Dale F; Fortin, David; Neuwelt, Edward A (2002) Chemotherapeutic dose intensification for treatment of malignant brain tumors: recent developments and future directions. Curr Neurol Neurosci Rep 2:216-24
Blakley, Brian W; Cohen, James I; Doolittle, Nancy D et al. (2002) Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001. Laryngoscope 112:1997-2001
Smith, Justine R; Rosenbaum, James T; Wilson, David J et al. (2002) Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement. Ophthalmology 109:1709-16
Muldoon, L L; Walker-Rosenfeld, S L; Hale, C et al. (2001) Rescue from enhanced alkylator-induced cell death with low molecular weight sulfur-containing chemoprotectants. J Pharmacol Exp Ther 296:797-805
Remsen, L G; Marquez, C; Garcia, R et al. (2001) Efficacy after sequencing of brain radiotherapy and enhanced antibody targeted chemotherapy delivery in a rodent human lung cancer brain xenograft model. Int J Radiat Oncol Biol Phys 51:1045-9
Doolittle, N D; Muldoon, L L; Brummett, R E et al. (2001) Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors. Clin Cancer Res 7:493-500
Osztie, E; Varallyay, P; Doolittle, N D et al. (2001) Combined intraarterial carboplatin, intraarterial etoposide phosphate, and IV Cytoxan chemotherapy for progressive optic-hypothalamic gliomas in young children. AJNR Am J Neuroradiol 22:818-23
Neuwelt, E A; Pagel, M A; Hasler, B P et al. (2001) Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model. Cancer Res 61:7868-74

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