The specific aim of this study is to quantify alterations in microvascular permeability of normal and neoplastic tissue by direct in vivo measurement of the extravasation of fluorescein-tagged dextran (molecular weight = 150,000) following local or systemic administration of vasoactive agents. These agents include amines (prostaglandins and leukotrienes), polypeptides (angiotensin, bradykinin, and vasopressin), catecholamines (epinephrine and norepinephrine) and glucose. Dose-response curves will be constructed for every agent. Experimental methods will involve growing normal (mature granulation) and neoplastic VX2 carcinoma) tissues in a transparent rabbit ear chamber prepared routinely in our laboratory. Once the tissue prepration is mature, fluorescein isothiocyanate (FITC)-tagged dextran molecule (molecular weight of 150,000) will be injected into the animal's circulation. Fifteen minutes later, a vasoactive agent will be administered locally or systemically. Resulting extravasation of FITC-dextran will be monitored and video recorded for up to three hours using an intravital fluorescene microscopy technique developed and tested in our laboratory. Stemic blood pressure of animals will be monitored in each experiment. In a limited number of experiments, microvascular pressure will be measured by opening the chamber carefully and inserting micropipette in desired blood vessels. The spatial and temporal concentration data will be used to calculate the interstitial diffusion coefficient and effective microvascular permeability using previously developed mathematical models. Theoretical work will involve development of mathematical models to quantify changes in microvascular transport and endothelial damages. Single capillary models will be extended to multiple capillaries, wherein the morphological and transport chracteristics of each capillary can be different. It is hoped that the results of this investigation using vasoactive agents as a probe will increase our fundamental understanding of the structural and functional differences between normal and neoplastic microcirculation and will aid in improving the current methods of cancer detection and treatment. (4)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036902-03
Application #
3174533
Study Section
Cardiovascular and Pulmonary Research B Study Section (CVB)
Project Start
1984-12-01
Project End
1987-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Carnegie-Mellon University
Department
Type
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Leunig, M; Yuan, F; Menger, M D et al. (1992) Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice. Cancer Res 52:6553-60
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Kaufman, E N; Jain, R K (1992) Effect of bivalent interaction upon apparent antibody affinity: experimental confirmation of theory using fluorescence photobleaching and implications for antibody binding assays. Cancer Res 52:4157-67
Kaufman, E N; Jain, R K (1991) Measurement of mass transport and reaction parameters in bulk solution using photobleaching. Reaction limited binding regime. Biophys J 60:596-610
Yuan, F; Baxter, L T; Jain, R K (1991) Pharmacokinetic analysis of two-step approaches using bifunctional and enzyme-conjugated antibodies. Cancer Res 51:3119-30
Baxter, L T; Jain, R K (1991) Transport of fluid and macromolecules in tumors. IV. A microscopic model of the perivascular distribution. Microvasc Res 41:252-72
Kaufman, E N; Jain, R K (1990) Quantification of transport and binding parameters using fluorescence recovery after photobleaching. Potential for in vivo applications. Biophys J 58:873-85

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