The microvasculature supplying a number of experimental tumors is hyperpermeable to circulating macromolecules. As a consequence, macromolecules enter and accumulate in tumors many times more rapidly than in normal tissues. However, fluorescence microscopy has shown that extravasated fluoresceinated dextran (FITC-D) tracers of MW greater than or equal to 70 kD remain in tumor stroma close to the vessels from which they leak and diffuse poorly in tumors, as compared with much small FITC-D (MW approximately 3 kD) which diffuse widely through tumors. These finding are relevant to the distribution of monoclonal antibodies and other macromolecules now being considered for tumor imaging and therapy. The goal of this proposal to investigate the permeability of tumor vessels to circulating macromolecules (MW greater than or equal to approximately 3 kD) and to compare the properties of hyperpermeable tumor vessels with those of healing wounds. First, we will determine to what extent the findings of vascular hyperpermeability can be generalized beyond a handful of transplantable animal carcinomas to other, more relevant models such as autochthonous animal and human tumors. We will also establish whether tumors, the host site into which they are planted, or both determine the extent of vascular permeability and the anatomic structure of the new microvasculature induced; i.e., lined by continuous, fenestrated or sinusoidal endothelium. Next, we will determine whether the blood vessels that supply tumors and healing wounds share a definable set of physical properties that regulate the influx, accumulation and distribution of circulating tracers. Finally, we will elucidate the ultrastructural basis of the hyperpermeability of tumor and wound vessels to macromolecular tracers. More formally, we seek to determine the following: 1. Influx, accumulation and distribution of macromolecular tracers in a spectrum of animal and xenografted human tumors, growing in different sites in syngeneic animals or nude mice. Distribution and identity of hyperpermeable tumor blood vessels. 2. Influx, accumulation and distribution of macromolecular tracers in autochthonous human tumors. Distribution and identity of hyperpermeable tumor blood vessels. 3. Properties of circulating macromolecules that affect their influx, accumulation and distribution in tumors and healing wounds. Comparison with monoclonal antibodies. 4. Mechanism(s) by which macromolecules extravasate from the leaky blood vessels of tumors and healing wounds.
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