This proposal focuses on the delivery of immunoconjugates to a model of human central nervous system metastatis in the nude rat. we have characterized the LX- 1 small cell lung carcinoma human tumor xenograft model in the nude rat with regard to permeability, growth characteristics, and survival times. We now propose to expand our current intracerebral tumor model using clonal populations of LX- 1 cells that stably express high or low amounts of the Lewis-y antigen for binding of monoclonal antibody (mAb) BR96. We hypothesize that these tumors will have similar growth and permeability characteristics to the parental LX- 1 model, but will have markedly different responses in the imaging and efficacy studies. In addition, these cell lines will provide a unique model to examine issues of tumor heterogeneity in imaging and therapy with immunoconjugates. We propose to examine the potential for specific imaging and diagnosis of intracerebral tumors using paramagnetic iron oxide particles conjugated to mAbs or mAb fragments as a tumor-specific contrast agent for magnetic resonance imaging. Pancarcinoma mAbs BR96 and L6, and the L6-F(ab')/2 and recombinant L6-sFv and BR96-sFv fragments, which may show reduced levels of non-specific binding compared to intact mAb, will be conjugated to the monocrystalline iron oxide nanoparticles (MIONs). We will then determine whether tumor-speclfic imaging can be attained using these agents, when delivery to intracerebral tumor is optimized with osmotic blood-brain barrier disruption (BBBD). The use of these MION antibodies conjugates offer the possibility of noninvasive assessment of tumor type and extent by adding specificity to an already sensitive MR imaging modality. In addition to the imaging studies, we will investigate the potential for therapy of intracerebral tumors using Doxorubicin and Pseudomonas exotoxin conjugated to the BR96 mAb or BR96- sFv fragment, respectively. We have the possibility for chemotherapy specifically targeted to brain tumors. The combination of an effective drug such as doxorubicin with tumor-specific localization and increased tumor delivery using osmotic BBBD is an innovative approach to brain turnor therapy with true practical application in the clinic. Clinical trials, based on previous blood-brain barrier program R01 funding, are resulting in durable tumor responses with no cognitive loss, particularly in CNS lymphoma patients. The proposed studies will further enhance these positive clinical results.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Jacobs, Tom P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Schools of Medicine
United States
Zip Code
Weinstein, Jason S; Varallyay, Csanad G; Dosa, Edit et al. (2010) Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab 30:15-35
Li, Xin; Rooney, William D; Várallyay, Csanád G et al. (2010) Dynamic-contrast-enhanced-MRI with extravasating contrast reagent: rat cerebral glioma blood volume determination. J Magn Reson 206:190-9
Thompson, Eric M; Dosa, Edit; Kraemer, Dale F et al. (2010) Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery 67:87-93
Jahnke, Kristoph; Muldoon, Leslie L; Varallyay, Csanad G et al. (2009) Efficacy and MRI of rituximab and methotrexate treatment in a nude rat model of CNS lymphoma. Neuro Oncol 11:503-13
Varallyay, Csanad G; Muldoon, Leslie L; Gahramanov, Seymur et al. (2009) Dynamic MRI using iron oxide nanoparticles to assess early vascular effects of antiangiogenic versus corticosteroid treatment in a glioma model. J Cereb Blood Flow Metab 29:853-60
Wu, Yingjen Jeffrey; Muldoon, Leslie L; Dickey, Dana Thomas et al. (2009) Cyclophosphamide enhances human tumor growth in nude rat xenografted tumor models. Neoplasia 11:187-95
Neuwelt, Edward A; Hamilton, Bronwyn E; Varallyay, Csanad G et al. (2009) Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int 75:465-74
Jahnke, Kristoph; Muldoon, Leslie L; Varallyay, Csanad G et al. (2009) Bevacizumab and carboplatin increase survival and asymptomatic tumor volume in a glioma model. Neuro Oncol 11:142-50
Jahnke, Kristoph; Kraemer, Dale F; Knight, Kristin R et al. (2008) Intraarterial chemotherapy and osmotic blood-brain barrier disruption for patients with embryonal and germ cell tumors of the central nervous system. Cancer 112:581-8
Stenstrom, David A; Muldoon, Leslie L; Armijo-Medina, Hector et al. (2008) N-acetylcysteine use to prevent contrast medium-induced nephropathy: premature phase III trials. J Vasc Interv Radiol 19:309-18

Showing the most recent 10 out of 58 publications