The overall goal of this project is to develop dynamic MRI methods, using macromolecular contrast media (MMCM) enhancement, for monitoring the response of tumors to inhibitors of angiogenesis. Our previous studies have shown that MMCM can be used with MRI to estimate fractional blood volume (fBV), as a measure of vascularity, and the endothelial transfer coefficient (KPS), as a measure of tumor vascular leakiness. The overall hypothesis is that inhibitors of angiogenesis alter the structure and function of tumor blood vessels, including their leakiness to macromolecular solutes, in ways that can be detected and quantified by dynamic MRI. The approach takes advantage of the well-documented macromolecular leakiness of tumor blood vessels. Planned studies will determine if the MR/measurements can serve as biomarkers of tumor angiogenesis and, when used early in the course of treatment, can predict the long-term response to antiangiogenic therapy. Our planned studies will determine the utility of the MRI methods in assessing angiogenesis inhibitors that act through vascular endothelial growth factor (VEGF) and other elements implicated in angiogenesis. They will also elucidate the effect of antiangiogenic drugs on the delivery of cytotoxic agents to tumor cells. Complementary fluorescence, confocal, and electron microscopic studies, with a focus on changes induced in endothelial cells, pericytes, and basement membranes of tumor vessels by angiogenesis inhibitors, will give insight into cellular changes underlying vascular functions assessed by the MRI methods. The MRI methods should facilitate the screening of angiogenesis inhibitors in preclinical models, should strengthen the design of clinical trials of antiangiogenic drugs - including trials using combinations of angiogenesis inhibitors and cytotoxic drugs, and ultimately should improve assessment of clinical responses to antiangiogenic therapies in cancer patients.
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