Can a Small-Molecular Gadolinium Contrast Agent be Applied Successfully with Dynamic MRI to Quantitatively Define Brain Tumor Microvascular Responses to Angiogenesis Inhibition? 1 Robert C. Brasch, MD, Axel Gossmann, MD, Thomas H. Helbich, MD, Nagato Kuriyama, MD, PhD Timothy P. L. Roberts, PhD, David M. Shames, MD, N. van Bruggen, PhD Michael F. Wendland, PhD, Mark A. Israel, MD RATIONALE AND OBJECTIVES Currently, there are intensive efforts to identify and develop imaging methods to characterize and grade tu- mors with respect to angiogenesis. Angiogenesis is essen- tial for tumor growth and metastases and is mediated by signaling molecules elaborated by tumors and tumor-asso- ciated inflammatory cells. Vascular endothelial growth factor (VEGF) is one of those angiogenic factors consid- ered to play a key role in the vascularization of both nor- mal and neoplastic tissue. VEGF is a potent and specific mitogen for endothelial cells and stimulates the full cas- cade of events required for angiogenesis. The VEGF polypeptide is simultaneously a vascular permeability fac- tor (VPF) having been shown to increase the permeability of microvessels to macromolecular solutes, including se- rum proteins, with a potency approximating 50,000 times that of histamine. Reported studies have demonstrated that systemic ad- ministration of anti-VEGF monoclonal antibody can in- hibit the growth of tumor xenografts, reduce the rate of tumor metastases, reduce overall tumor vascularity, and reduce the permeability to macromolecular solutes of tu- mor microvessels. However, the macromolecular perme- ability response to anti-VEGF antibody has been demon- strated in xenografts from tumor types arising outside the central nervous system (CNS). Similar observations may or may not extend to CNS tumors. Furthermore, the CNS has unique vascular characteristics resulting in a relatively impermeable brain/blood barrier, at least for normal neu- ral tissue. Accordingly, macromolecular contrast media that might be well suited for estimating tumor hyperper- meability in non-neural tissues may not be necessary or well suited for CNS evaluations, and vice versa. If shown feasible in an orthotopic glial brain tumor model, the use of quantitative dynamic MRI enhanced using a small molecular gadolinium contrast agent could be applied immediately to clinical testing of anti- angiogenesis drugs and to the routine evaluation of pa- tients. MATERIALS AND METHODS In this study we evaluated the effects of a neutralizing anti-vascular endothelial growth factor (anti-VEGF) anti- body on tumor microvascular permeability, a proposed indicator of angiogenesis, and tumor growth in a rodent malignant glioma model. A dynamic contrast enhanced magnetic resonance imaging (MRI) technique, permitting non-invasive in vivo and in situ assessment of potential Acad Radiol 2002; 9(suppl 2):S326 –S327 1 From the Center for Pharmaceutical and Molecular Imaging, Department of Radiology (R.C.B., A.G., T.H.H., T.P.L.R., D.M.S., M.F.W.), and Depart- ment of Neurological Surgery (N.K., M.A.I.), University of California, San Francisco, Calif; and Department of Neuroscience, Genentech Inc, South San Francisco, Calif (N.B.). Supported by funds received from the National Cancer Institute, grant CA64602 and from the Cancer Research Fund, State of California, under interagency agreement 97-12013 (University of California contract 98-00924V). Address correspondence to R.C.B. © AUR, 2002 S326