These studies are designed to obtain information about drug delivery in experimental brain tumors. Our previous work has shown low rates o blood-to-tissue transport of water soluble compounds in experimental brain tumors.
The specific aims are: 1) to study the effects of corticosteroids and x-irradiation on blood flow and blood-to-tissue transport; 2) to study methods that may increase the rate of blood-to-tissue transport in brain tumors (hyperosmotic disruption, hypertension, hypercapnia, hyperthermia and dimethyl sulfoxide); 3) to develop an in vivo method to measure the rate of blood-to-tissue transport using computed tomographic (CT) scanning; 4) to measure the rates of blood-to-tissue transport of several commonly used cancer chemotherapeutic drugs, and; 5) to correlate the rate of blood-to-tissue transport with ultrastructural features of capillaries and measure the surface area of capillaries available for transcapillary exchange. Blood flow will be measured with Kety-Schmidt equations. The rate of blood-to-tissue transport will be measured with alpha-aminoisobutyric acid (which has unidirectional blood-to-tissue transport) or with the slope-intercept method of data analysis for compounds with bi-directional capillary transport. Tissue concentrations of radiolabeled drugs will be measured by quantitative autoradiography. The surface area of tumor capillaries will be measured after staining the capillaries with Factor VIII/von Willebrand antiserum and peroxidase-antiperoxidase. Since most chemotherapeutic drugs are water soluble, and since water soluble compounds have low rates of transcapillary transport in brain tumors, we hope to find methods with which drug delivery can be increased to brain tumors. In order for these methods to be applied to humans, a method to measure the rate of transcapillary transport in vivo will be needed, for whic we plan to use the CT scanner and the slope-intercept methd of graphical analysis. We also plan to study the transport properties of brain tumor capillaries to see if the rate of transcapillary transport of chemotherapeutic drugs can be predicted, based on either the water solubility or molecular size of the drug. If these objectives can be accomplished, they will have direct applicability in the treatment of human brain tumor patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Modified Research Career Development Award (K04)
Project #
5K04NS000814-04
Application #
3074693
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1983-07-01
Project End
1988-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Evanston Hospital
Department
Type
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60201
Groothuis, D R; Vriesendorp, F J; Kupfer, B et al. (1991) Quantitative measurements of capillary transport in human brain tumors by computed tomography. Ann Neurol 30:581-8
Fross, R D; Warnke, P C; Groothuis, D R (1991) Blood flow and blood-to-tissue transport in 9L gliosarcomas: the role of the brain tumor model in drug delivery research. J Neurooncol 11:185-97
Groothuis, D R; Lapin, G D; Vriesendorp, F J et al. (1991) A method to quantitatively measure transcapillary transport of iodinated compounds in canine brain tumors with computed tomography. J Cereb Blood Flow Metab 11:939-48
Groothuis, D R; Warkne, P C; Molnar, P et al. (1990) Effect of hyperosmotic blood-brain barrier disruption on transcapillary transport in canine brain tumors. J Neurosurg 72:441-9
Warnke, P C; Phillips, A; Bernstein, L P et al. (1989) The somatosensory evoked potential as a noninvasive method to determine flow rates for hyperosmotic disruption of the blood-brain barrier. Neurosurgery 25:405-11
Vriesendorp, F J; Peagram, C; Bigner, D D et al. (1987) Concurrent measurements of blood flow and transcapillary transport in xenotransplanted human gliomas in immunosuppressed rats. J Natl Cancer Inst 79:123-30
Warnke, P C; Friedman, H S; Bigner, D D et al. (1987) Simultaneous measurements of blood flow and blood-to-tissue transport in xenotransplanted medulloblastomas. Cancer Res 47:1687-90
Vriesendorp, F J; Pasternak, J F; Groothuis, D R (1987) The effect of systemic arterial hypertension on blood-to-tissue transport in experimental gliomas. J Neurooncol 5:289-97
Warnke, P C; Molnar, P; Bigner, D D et al. (1987) Intravenous adenosine selectively increases blood flow to xenotransplanted intracerebral gliomas. Neurology 37:1870-3
Trommer, B L; Groothuis, D R; Pasternak, J F (1987) Quantitative analysis of cerebral vessels in the newborn puppy: the structure of germinal matrix vessels may predispose to hemorrhage. Pediatr Res 22:23-8

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