Purpose-Inhibition of 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, was observed, suggesting pruning of immature vessels lacking pericytes. Tumor vessel permeability was also significantly decreased and intratumoral oxygen tension increased two and five days after bevacizumab due 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.
Background-We hypothesized that vascular endothelial growth factor (VEGF) contributes to autocrine stimulation of neuroblastoma and that inhibition of its signaling pathway contributes to the anticancer activity of bevacizumab, an anti-VEGF monoclonal antibody.
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