The purpose of the proposed project is to study the mechanisms of malignant behavior in glioma cells. We will study expression of the peripheral benzodiazepine receptor (PBR) and activation of proto-oncogenes which have been implicated in the process of glial cell oncogenesis. Our hypotheses are: 1) the malignant phenotype in glioma cells is dependent on activation of the proto-oncogene c-myc by PDGF-type signalling pathways (c-sis/PDGF-beta and Stem Cell Factor), 2) expression of the PBR, a putative marker for glial tumor cells, contributes to the malignant behavior of the cells, and 3) PBR may be expressed by the actions of these proto-oncogenes. Malignant glial tumors remain a devastating disease which responds only transiently to current therapies. Because of the selective expression of PBR by malignant glial tumors (Broaddus and Bennett, 1990), this binding site is a candidate for selectively imaging tumor cells and targeting therapies at them.
The specific aims of this project encompass plans to demonstrate localization of this component to glial tumor cells using in situ hybridization, a technique which allows much higher precision than has been used thus far in histological studies of PBR expression by tumor cells. Focussing on mechanisms of malignant transformation, we will carry out studies to show an association of changes in c-myc and PBR expression with alteration of malignant characteristics glioma cells. Finally, we propose to use antisense gene sequences to demonstrate dependence of malignant phenotype on expression of c-myc, putative autocrine growth factor systems (c-sis and SCF) and PBR. These studies will provide better understanding of the mechanisms involved in the malignant progression of glial cells, and help define the potential utility of the PBR as a target for imaging and directing cytotoxic strategies. Successful use of antisense oligonucleotide sequences to reverse glial tumor cell proliferation will also have potential applicability to gene therapy strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001766-02
Application #
2259929
Study Section
NST-2 Subcommittee (NST)
Project Start
1994-09-20
Project End
1999-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Chen, Zhi-Jian; Broaddus, William C; Viswanathan, Raju R et al. (2002) Intraparenchymal drug delivery via positive-pressure infusion: experimental and modeling studies of poroelasticity in brain phantom gels. IEEE Trans Biomed Eng 49:85-96
Broaddus, W C; Gillies, G T; Kucharczyk, J (2001) Minimally invasive procedures. Advances in image-guided delivery of drug and cell therapies into the central nervous system. Neuroimaging Clin N Am 11:727-35
Haar, P J; Stewart, J E; Gillies, G T et al. (2001) Quantitative three-dimensional analysis and diffusion modeling of oligonucleotide concentrations after direct intraparenchymal brain infusion. IEEE Trans Biomed Eng 48:560-9
Prabhu, S S; Broaddus, W C; Oveissi, C et al. (2000) Determination of intracranial tumor volumes in a rodent brain using magnetic resonance imaging, Evans blue, and histology: a comparative study. IEEE Trans Biomed Eng 47:259-65
Brust, D; Feden, J; Farnsworth, J et al. (2000) Radiosensitization of rat glioma with bromodeoxycytidine and adenovirus expressing herpes simplex virus-thymidine kinase delivered by slow, rate-controlled positive pressure infusion. Cancer Gene Ther 7:778-88
Fillmore, H L; Shurm, J; Furqueron, P et al. (1999) An in vivo rat model for visualizing glioma tumor cell invasion using stable persistent expression of the green fluorescent protein. Cancer Lett 141:9-19
Prabhu, S S; Broaddus, W C; Gillies, G T et al. (1998) Distribution of macromolecular dyes in brain using positive pressure infusion: a model for direct controlled delivery of therapeutic agents. Surg Neurol 50:367-75;discussion 375
Broaddus, W C; Chen, Z J; Prabhu, S S et al. (1997) Antiproliferative effect of c-myc antisense phosphorothioate oligodeoxynucleotides in malignant glioma cells. Neurosurgery 41:908-15
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