4.7 Article

Anti-VEGF Antibodies Mitigate the Development of Radiation Necrosis in Mouse Brain

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CLINICAL CANCER RESEARCH
卷 20, 期 10, 页码 2695-2702

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-1941

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  1. NIH [R01 CA155365, R01 CA174966, R01 CA140220-01]
  2. National Cancer Institute Comprehensive Cancer Center [P30 CA091842]
  3. BarnesJewish Hospital Foundation Cancer Frontier Fund
  4. Alvin J. Siteman Cancer Center
  5. Elekta Instruments AB

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Purpose: To quantify the effectiveness of anti-VEGF antibodies (bevacizumab and B20-4.1.1) as mitigators of radiation-induced, central nervous system (brain) necrosis in a mouse model. Experimental Design: Cohorts of mice were irradiated with single-fraction 50-or 60-Gy doses of radiation targeted to the left hemisphere (brain) using the Leksell Perfexion Gamma Knife. The onset and progression of radiation necrosis were monitored longitudinally by in vivo, small-animal MRI, beginning 4 weeks after irradiation. MRI-derived necrotic volumes for antibody (Ab)-treated and untreated mice were compared. MRI results were supported by correlative histology. Results: Hematoxylin and eosin-stained sections of brains from irradiated, non-Ab-treated mice confirmed profound tissue damage, including regions of fibrinoid vascular necrosis, vascular telangiectasia, hemorrhage, loss of neurons, and edema. Treatment with the murine anti-VEGF antibody B20-4.1.1 mitigated radiation-induced changes in an extraordinary, highly statistically significant manner. The development of radiation necrosis in mice under treatment with bevacizumab (a humanized anti-VEGF antibody) was intermediate between that for B20-4.1.1-treated and non-Ab-treated animals. MRI findings were validated by histologic assessment, which confirmed that anti-VEGF antibody treatment dramatically reduced late-onset necrosis in irradiated brain. Conclusions: The single-hemispheric irradiation mouse model, with longitudinal MRI monitoring, provides a powerful platform for studying the onset and progression of radiation necrosis and for developing and testing new therapies. The observation that anti-VEGF antibodies are effective mitigants of necrosis in our mouse model will enable a wide variety of studies aimed at dose optimization and timing and mechanism of action with direct relevance to ongoing clinical trials of bevacizumab as a treatment for radiation necrosis.

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