Assessment of antiangiogenic therapy in a nude murine hepatocellular carcinoma model with real-time gray-scale contrast-enhanced ultrasonography

Abstract

Objective To assess intratumoral microvascular perfusion changes by real-time gray-scale contrast-enhanced ultrasonography(CEUS) in a nude murine hepatocellular carcinoma model treated with angiogenesis inhibitor,and to investigate the applicative value of quantitative analysis of CEUS. Methods Human hepatocellular carcinoma xenograft model was established in thirty nude mice subcutaneously. Fifteen nude mice were treated with an inhibitor of vascular endothelial growth factor receptors (pazopanib) by oral administration and fifteen nude mice were set as control. Volume measurement and CEUS were performed 3 days before treatment, 7 days, 14 days and 21 days after treatment, respectively. Regions of interest within tumors were analyzed off-line to perform time-intensity curves and determine CEUS parameters. The relation between CEUS parameters and necrosis index of pathology were investigated. Results The relative tumor proliferation rate in the treatment group was 41% on 21 days after treatment. Increased signal intensity (ISI),area under the curve (AUC) and blood flow coefficient (BF) were lower in the treatment tumors than those in the control tumors,in addition slope of decrease to half of peak (a2) and slope of rise time (a3) was higher (P<0.05). CEUS parameters correlated with the volume growth rate in treatment tumors,respectively (P<0.05). A3 and ISI were negative correlated with necrosis index (r=-0.54, P=0.008; r=-0.46, P=0.027). Conclusions Real-time gray-scale CEUS reflects changes of microvascular perfusion in tumors objectively, which is potential in monitoring tumor vascular response to antiangiogenic therapy. Key words: Ultrasonography; Microbubbles; Liver neoplasms, experimental; Neovascularization, pathologic