Malignant brain tumors are almost uniformly fatal. Brain tumor chemotherapy has been based on empiric principles rather than rational understanding of drug delivery processes, and has contributed little to improved quality or length of life in these patients. Our goal is to develop operational expressions to predict the amount of drug delivered to a brain tumor, and thus individualize chemotherapy for brain tumor patients. To do this, it is necessary to know properties of the drugs being used, and to measure certain physiological properties of the tumors being treated.
Four Specific Aims will quantitatively study drug delivery parameters, and determine their effect on operational equations to predict tumor drug exposure.
These Specific Aims are: 1) to determine if there is a linear relationship between the rate of transcapillary transport and the physicochemical properties of a drug, 2) to determine whether a similar relationship exists between drug properties and transmembrane transport into brain tumor cells, 3) to determine if diffusion, either within a tumor or in brain around tumor, limits tumor cell drug exposure, and, 4) to determine if commonly used treatment modalities for brain tumors (e.g., dexamethasone or radiation) affect drug delivery parameters. Since delivery of both lipid and water-soluble drugs is limited in many individual brain tumors, Specific Aim 5 seeks to explore ways of selectively increasing tumor drug delivery.
Specific Aim 6 seeks to develop operational expressions to express the formation of tumor-associated brain edema, and determine how treatment of this edema affects drug delivery processes. These studies utilize well established rat and dog brain tumor models in vivo, and rat and human glioma cell lines in vitro. We will use three experimental methodologies to obtain quantitative measurements of drug concentration: quantitative autoradiography (QAR), high performance liquid chromatography (HPLC), and computed tomographic (CT) techniques that were developed in our laboratory at Evanston Hospital.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Experimental Therapeutics Subcommittee 1 (ET)
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Evanston Hospital
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Groothuis, Dennis R; Vavra, Michael W; Schlageter, Kurt E et al. (2007) Efflux of drugs and solutes from brain: the interactive roles of diffusional transcapillary transport, bulk flow and capillary transporters. J Cereb Blood Flow Metab 27:43-56
Ali, Mir J; Navalitloha, Yot; Vavra, Michael W et al. (2006) Isolation of drug delivery from drug effect: problems of optimizing drug delivery parameters. Neuro Oncol 8:109-18
Navalitloha, Yot; Schwartz, Erica S; Groothuis, Elizabeth N et al. (2006) Therapeutic implications of tumor interstitial fluid pressure in subcutaneous RG-2 tumors. Neuro Oncol 8:227-33
Vavra, Michael; Ali, M Jaffer; Kang, Eric W-Y et al. (2004) Comparative pharmacokinetics of 14C-sucrose in RG-2 rat gliomas after intravenous and convection-enhanced delivery. Neuro Oncol 6:104-12
Groothuis, D R (2000) The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. Neuro Oncol 2:45-59
Groothuis, D R; Benalcazar, H; Allen, C V et al. (2000) Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration. Brain Res 856:281-90
Schlageter, K E; Molnar, P; Lapin, G D et al. (1999) Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties. Microvasc Res 58:312-28
Molnar, P P; O'Neill, B P; Scheithauer, B W et al. (1999) The blood-brain barrier in primary CNS lymphomas: ultrastructural evidence of endothelial cell death. Neuro Oncol 1:89-100
Groothuis, D R; Ward, S; Itskovich, A C et al. (1999) Comparison of 14C-sucrose delivery to the brain by intravenous, intraventricular, and convection-enhanced intracerebral infusion. J Neurosurg 90:321-31
Molnar, P; Fekete, I; Schlageter, K E et al. (1999) Absence of host-site influence on angiogenesis, blood flow, and permeability in transplanted RG-2 gliomas. Drug Metab Dispos 27:1085-91

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