There is now considerable evidence that dynamic contrast agent-enhanced magnetic resonance imaging (MRI) data, when analyzed with appropriate pharmacokinetic models, are able to provide quantitative information regarding the vascular volume fraction (fvv), permeability-surface area product (PS), and contrast agent reflux rate (kR) in tumors. If shown to be accurate, such non-invasive measures will be highly useful in evaluating the efficacy of antiangiogenic therapies and in predicting how well chemotherapeutic agents will penetrate into tumors through diffusive and convective processes. Limited, and often contradictory, studies have been performed to date to correlate MRI-derived in vivo measures of fvv, PS, and kR with existing """"""""gold standards"""""""" such as immunohistochemistry-based measures of microvessel density and vascular permeability. Furthermore, rigorous comparisons of MRI-derived measures obtained using FDA-approved low molecular weight contrast media with those obtained using theoretically advantageous higher molecular weight media currently in clinical trials are limited. Such studies are needed to establish the limitations of using each class of contrast media in assessing fvv, PS, and kR. These issues must be resolved prior to the application of such promising non-invasive measures to clinical monitoring of the efficacy of antiangiogenic therapy. The overall goals of this project are to 1) demonstrate that accurate in vivo quantitative measures of fvv, PS, and kR can be obtained via single and/or dual tracer pharmacokinetic modeling of dynamic contrast agent-enhanced MRI data, and 2) correlate such measures, in both animal models and human studies, with other surrogate markers of angiogenesis, including expression of specific angiogenic factors, proteases, rates of endothelial cell apoptosis, and endothelial cell-specific markers.
The specific aims i n this project are: 1) correlation of single and dual tracer pharmacokinetic measures of fvv, PS, and kR obtained using high, medium, and low molecular weight contrast agents with immunohistochemical and radionuclide determinations of microvessel density and vascular permeability; 2) acquisition of longitudinal pharmacokinetic measures of fvv, PS, and kR in subcutaneously implanted tumors treated with antiangiogenic therapies, and correlation of these measures with other surrogate markers of angiogenesis and vascular permeability; and 3) acquisition of longitudinal pharmacokinetic measures in patients enrolled in clinical trials of antiangiogenic drugs, and correlation of these measures with other invasive surrogate markers of angiogenesis.
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