Rapamycin-induced tumor vasculature remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation

Adrianne L. Myers, W. Shannon Orr, Jason W. Denbo, Catherine Y. Ng, Junfang Zhou, Yunyu Spence, Jianrong Wu, Andrew M. Davidoff

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Purpose: Rapamycin inhibits vascular endothelial growth factor expression. Vascular endothelial growth factor is a tumor-elaborated protein that stimulates neovascularization. This inhibition can cause transient " normalization" of the generally dysfunctional tumor vasculature, resulting in improved tumor perfusion and oxygenation. We hypothesized that this may potentiate the antitumor effects of adjuvant ionizing radiation. Methods: Mice bearing orthotopic Rh30 alveolar rhabdomyosarcomas were treated with rapamycin (5 mg/kg intraperitoneally daily ×5). Tumors were then evaluated for changes in intratumoral oxygenation, perfusion, vessel permeability, and microvessel density. Additional tumor-bearing mice were treated with 5 doses of rapamycin, irradiation (4 Gy), or 5 doses of rapamycin with irradiation administered on the first or sixth day of rapamycin treatment. Results: Although tumor vessel permeability changed only minimally, microvessel density decreased (3153 ± 932 vs 20,477 ± 3717.9 pixels per high-power field), whereas intratumoral oxygenation increased significantly (0.0385 ± 0.0141 vs 0.0043 ± 0.0023 mm Hg/mm 3) after 5 doses of rapamycin. Contrast-enhanced ultrasound demonstrated a significantly increased rate of change of signal intensity after 5 days of rapamycin, suggesting improved intratumoral perfusion. Tumor volume 14 days after treatment was smallest in mice treated with the combination of rapamycin given before irradiation. Conclusion: Combination therapy with rapamycin given before irradiation to normalize the tumor vasculature, thereby improving tumor oxygenation, increased the sensitivity of alveolar rhabdomyosarcoma xenografts to adjuvant irradiation.

Original languageEnglish (US)
Pages (from-to)183-189
Number of pages7
JournalJournal of Pediatric Surgery
Volume47
Issue number1
DOIs
StatePublished - Jan 2012

Bibliographical note

Funding Information:
This work was supported by the Assisi Foundation of Memphis , the US Public Health Service Childhood Solid Tumor Program Project grant number CA23099 , the Cancer Center Support grant number 21766 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities.

Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.

Keywords

  • Ionizing radiation
  • Rapamycin
  • Rhabdomyosarcoma
  • VEGF inhibition

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