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

Abstract

Purpose To quantify the effectiveness of anti-VEGF antibodies (bevacizumab and B20-4.1.1) as mitigators of radiation-induced, CNS (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 four weeks post-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.

Vascular Endothelial Growth Factor Enhanced the Angiogenesis Response of Human Umbilical Cord-Derived Mesenchymal Stromal Cells in a Rat Model of Radiation Myelopathy

“…However, contrary to previous studies, we found that VEGF had additional beneficial effects to UC-MSCs in the present study. The milder irradiation damage to spinal cord in our study may account for the different results from those of previous reports, which showed profound tissue damage including fibrinoid vascular necrosis, vascular telangiectasia, hemorrhage, loss of neurons, and edema [35][36][37][38][39]. Anti-VEGF therapy seems more effective in the severe irradiation central nervous system damage such as brain necrosis, and pro-VEGF therapy seems more effective in the mild irradiation central nervous system damage such as in the present study.…”

“…The newly developed vessels are leaky and further perpetuate edema and blood brain barrier dysfunction [34]. Anti-VEGF antibodies such as bevacizumab have been demonstrated as an effective therapy to mitigate irradiation induced central nervous system necrosis of clinical patients [35][36][37][38] and animal models [39]. These studies demonstrated that bevacizumab significantly reduced the abnormalities found in MRI analysis and improved cognitive function.…”

The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model

“…The necrotic volume was calculated using a pixel-intensity-comparison method previously described (Jiang et al 2014a), which primarily measures edema and breakdown of the blood-brain-barrier. This method involved taking the ratio of intensities of a single pixel on the exposed hemisphere to the average of a 5 × 5 pixel matrix on the contralateral side centered in the same anatomic location.…”

“…Small animal models of radiation-induced necrosis, however, represent a useful means to study this treatment related complication. Although it has been established that the radiation-induced necrosis in small animals is representative of the histological features observed in patients (Jiang et al 2014a, Jiang et al 2014b, Jiang et al 2015, Jost et al 2009, Perez-Torres et al 2014, Perez-Torres et al 2015), a limited amount of information exists on the temporal and spatial disease progression. Using stereotactic radiotherapy in mice, the time course of necrotic volumes have been measured with MRI for nine weeks after the onset of necrosis for 60-, 50-, and 45-Gy treatments (Jiang et al 2015).…”

Intrakraniyal Tumörlerin Tedaviye Yanitinin Radyolojik Olarak Degerlendirilmesi

“…RT'den aylar-yıllar sonra, genellikle de tedavi sonrası 18-24 ay sonra ortaya çıkar. VEGF ekspresyonundaki artış ile ilişkili olduğu ve dolayısıyla anti-VEGF anti- korlarının (bevacizumab) radyasyon nekrozunun ilerlemesini yavaşlattığı gösterilmiştir [43,44]. RN gelişimi, total sağkalımı etkilememektedir [40].…”