Improved Intratumoral Oxygenation Through Vascular Normalization Increases Glioma Sensitivity to Ionizing Radiation
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN (United States)
- Department of Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN (United States)
- Animal Imaging Center, St. Jude Children's Research Hospital, Memphis, TN (United States)
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN (United States)
- Department of Hematology/Oncology, University College London, London (United Kingdom)
- Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN (United States)
- Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN (United States)
Purpose: Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, thus, the antiglioma efficacy of ionizing radiation. Methods and Materials: Orthotopic U87 xenografts were treated with either continuous interferon-beta (IFN-beta) or bevacizumab, alone, or combined with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; the tumor vasculature using immunohistochemical staining, and tumor oxygenation using hypoxyprobe staining. Results: Both IFN-beta and bevaziumab profoundly affected the tumor vasculature, albeit with different cellular phenotypes. IFN-beta caused a doubling in the percentage of area of perivascular cell staining, and bevacizumab caused a rapid decrease in the percentage of area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab, the effect was transient, being lost by 5 days. Administration of IFN-beta or bevacizumab before RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-beta or bevacizumab or 5 days after bevacizumab. Conclusion: Bevacizumab and continuous delivery of IFN-beta each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the antitumor activity of ionizing radiation. Additional investigation into the use and timing of these and other agents that modify the vascular phenotype, combined with RT, is warranted to optimize cytotoxic activity.
- OSTI ID:
- 21372224
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Vol. 76, Issue 5; Other Information: DOI: 10.1016/j.ijrobp.2009.12.010; PII: S0360-3016(09)03674-8; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
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