Bevacizumab-induced tumor vessel remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation

Abstract

Purpose Inhibition of vascular endothelial growth factor (VEGF) may effect transient “normalization” of tumor vasculature by pruning immature vessels, resulting in improved tumor perfusion and oxygenation. This may improve the efficacy of adjuvant ionizing radiation (IR). We tested this hypothesis using bevacizumab, an anti-VEGF antibody, in rhabdomyosarcoma (RMS) xenografts. Methods Mice bearing orthotopic alveolar RMS xenografts were treated with a single dose of bevacizumab, IR, or a combination of the two on different schedules. Tumors were then evaluated for changes in microvessel density, vessel maturity, vessel permeability, intratumoral oxygenation, as well as altered growth. Results After bevacizumab treatment, a significant decrease in tumor microvessel density and a significant increase in tumor vessel maturity, defined as the ratio of pericytes to endothelial cells, were observed, suggesting pruning of immature vessels lacking pericytes. Tumor vessel permeability was also significantly decreased and intratumoral oxygen tension increased 2 and 5 days after bevacizumab owing to a transient improvement in tumor perfusion. Treatment with IR 2 or 5 days after bevacizumab resulted in the greatest antitumor activity. Conclusion Our findings support the hypothesis that VEGF inhibition with bevacizumab transiently normalizes the dysfunctional vasculature of RMS xenografts, improving tumor oxygenation and increasing tumor sensitivity to adjuvant IR.