Can a Small-Molecular Gadolinium Contrast Agent be Applied Successfully with Dynamic MRI to Quantitatively Define Brain Tumor Microvascular Responses to Angiogenesis Inhibition?

Abstract

Currently, there are intensive efforts to identify and develop imaging methods to characterize and grade tumors with respect to angiogenesis. Angiogenesis is essential for tumor growth and metastases and is mediated by signaling molecules elaborated by tumors and tumor-associated inflammatory cells. Vascular endothelial growth factor (VEGF) is one of those angiogenic factors considered to play a key role in the vascularization of both normal and neoplastic tissue. VEGF is a potent and specific mitogen for endothelial cells and stimulates the full cascade of events required for angiogenesis. The VEGF polypeptide is simultaneously a vascular permeability factor (VPF) having been shown to increase the permeability of microvessels to macromolecular solutes, including serum proteins, with a potency approximating 50,000 times that of histamine. Reported studies have demonstrated that systemic administration of anti-VEGF monoclonal antibody can inhibit the growth of tumor xenografts, reduce the rate of tumor metastases, reduce overall tumor vascularity, and reduce the permeability to macromolecular solutes of tumor microvessels. However, the macromolecular permeability response to anti-VEGF antibody has been demonstrated 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 neural tissue. Accordingly, macromolecular contrast media that might be well suited for estimating tumor hyperpermeability 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 antiangiogenesis drugs and to the routine evaluation of patients.