In its journey from the blood stream to cancer cells, a therapeutic agent encounters two barriers: the microvascular wall and the interstitium. The overall goal of our research is to develop a quantitative understanding of these two barriers to transport in tumors, and to develop novel strategies to overcome these barriers for improved cancer detection and treatment. More specifically, the aims for this renewal project are (1) to characterize binding kinetics in vivo between monoclonal antibodies and tumor-associated antigens and (2) to optimize two-step approaches for antibody-mediated delivery. Transport of fluorescently labelled molecules of interest will be measured in normal tissue and human tumors grown in the dorsal chamber in immunodeficient mice using two techniques developed in our laboratory: dual-fluorescence intravital microscopy (DFIM) and fluorescence recovery after photobleaching (FRAP). We will analyze these data using appropriate mathematical models. These models will also be used to develop guidelines for optimal dose and schedule of therapeutic agents. The proposed investigation is a logical extension of our previous research on the transport of nonspecific molecules in the rabbit ear chamber preparation. This renewal project will provide novel and -crucial data on the movement of anti-tumor monoclonal antibodies in human tumor xenografts. It not only represents a major step towards a fundamental understanding of transport and binding in tumors, but is also essential to improve the delivery of novel as well as conventional anti-tumor agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA036902-10
Application #
3174531
Study Section
Special Emphasis Panel (SSS (R6))
Project Start
1984-01-01
Project End
1993-11-30
Budget Start
1993-01-20
Budget End
1993-11-30
Support Year
10
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Yuan, F; Leunig, M; Berk, D A et al. (1993) Microvascular permeability of albumin, vascular surface area, and vascular volume measured in human adenocarcinoma LS174T using dorsal chamber in SCID mice. Microvasc Res 45:269-89
Boucher, Y; Jain, R K (1992) Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res 52:5110-4
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
Kaufman, E N; Jain, R K (1992) In vitro measurement and screening of monoclonal antibody affinity using fluorescence photobleaching. J Immunol Methods 155:1-17
Baxter, L T; Yuan, F; Jain, R K (1992) Pharmacokinetic analysis of the perivascular distribution of bifunctional antibodies and haptens: comparison with experimental data. Cancer Res 52:5838-44
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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