The central hypothesis of the current study is that the inadequate response of solid tumors to available therapeutic agents is due to vascular and interstitial transport barriers. These barriers prevent relevant agents from reaching the tumors uniformly and in adequate quantities. Widely studied cellular parameters, such as multidrug resistance and heterogeneous expression of antigen alone cannot explain the failure to treat solid tumors successfully. Therefore, our goal is to understand the fundamental nature of these barriers in human and rodent tumors, to overcome them or to exploit them. Quantitative understanding of physiological phenomena will be developed at the microcirculatory level in solid tumors, where the barriers exist and exert their influence on the uptake and distribution of metabolites and anti-cancer agents. Four unique yet complementary approaches will be used in our research: (i) a macroscopic approach using tissue-isolated tumors to study input/output relationships, (ii) a microscopic approach to directly visualize the events in the tumor microcirculation; (iii) in vitro characterization of deformability and adhesion of cells; and (iv) mathematical modeling to predict new directions of research and to validate existing data. These four approaches are intertwined in six projects: (i) tumor blood flow; (ii) metabolic microenvironment; (iii) transport of fluid and interstitial hypertension; (iv) transport of small and large molecules; (v) transport of cells; and (vi) heat transfer. Several strategies are proposed to overcome physiological barriers and to increase the uptake of therapeutic agents by tumors. These include fractionated radiation to reduce interstitial pressure and two-step approaches utilizing a combination of high molecular agents (i.e., monoclonal antibodies) and low molecular weight agents (prodrugs, haptens) to improve drug delivery. Mathematical modelling will be used to optimize drug parameters (molecular weight, binding kinetics) and treatment scheduling, as well as to provide a rational basis for experimental design. A central feature of the present application is the interplay between animal experiments, clinical investigations, and mathematical modelling. State-of-the-art technology will be applied to study in vivo microcirculation in human tumor xenograft preparation recently developed in our laboratory for the severe combined immunodeficient (SCID) mice. A new technique of fluorescence ratio imaging will be used to characterize the metabolic environment of tumors, with special attention to the role and distribution of pH. The hypothesis that tumor interstitial pressure is an important prognostic factor for tumor treatment and for tumor localization during needle biopsy will be tested in human tumors, both in situ and grown as xenografts. Delivery of activated lymphocytes will be studied by direct visualization in normal and tumor microcirculations and related to their adhesiveness and deformability. Finally, a mathematical model for the temperature distribution in tumors based on their vascular architecture will be developed and tested experimentally. The proposed comprehensive and systematic studies should provide new and important insights into the tumor pathophysiology, and possible strategies for cancer detection and treatment.
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