Quantitative imaging techniques for the assessment of tumor microvasculature

Vascular endothelial growth factor (VEGF) and its receptors VEGF-receptor 1 (VEGF-R1) and VEGF-receptor 2 (VEGF-R2) have been shown to play a major role in tumor angiogenesis. A number of conventional therapeutic agents and gene therapy strategies have been employed as specific inhibitors of VEGF and have been proposed as potential anti-tumoral, anti-angiogenesis agents. Because of these recently developed strategies for inhibiting tumor growth and metastasis through microvascular growth suppression, repetitive, non-invasive imaging of tumor angiogenesis and microvascular blood flow has become an important investigational tool for evaluating the effects of angiogenesis suppressing agents. Contrast enhanced computed tomography is currently used to identify and define the morphology of tumors. Likewise, ultrasound has been used for many years to diagnose and characterize parenchymal lesions such as solid tumors. There are currently a number of stabilized microbubble preparations either actively on the market or in late phase clinical trials that, when injected intravascularly, serve as ultrasound contrast enhancement agents. Using a novel combination of pulse sequences estimates of regional flow velocity and quantitative estimates of blood flow can be made. The purpose of this series of studies was to use new methods of both dynamic contrast enhanced computed tomography and contrast enhanced ultrasound to develop non-invasive methods for quantifying and serially monitoring tumor blood flow and permeability. These methods of evaluation were used to repeatedly monitor tumors during uninhibited growth and during anti-angiogenesis therapy. Both dynamic contrast enhanced computed tomography and ultrasound were able to provide anatomic and functional information regarding tumor microcirculation. Measures made with these novel imaging strategies correlated with gold standard techniques. The results of this series of studies will act as a cornerstone for future studies directed at characterizing tumors by their microcirculation, permeability and flow characteristics, and in repetitive assessment of tumor response to anti-angiogenesis agents.