Intra-arterial bevacizumab with blood brain barrier disruption in a glioblastoma xenograft model
Jan-Karl Burkhardt, Alejandro Santillan, Christoph P. Hofstetter, Paul Christos, Nick Berry, Benjamin J. Shin, Conor P. Foley, Demirkan B. Gürsel, Douglas J. Ballon, Y. Pierre Gobin and John A. Boockvar
Purpose: In this study we investigated the treatment response and survival of intra-arterial (IA) compared to intra-peritoneal (IP) delivery of bevacizumab (BV) in a glioblastoma (GBM) xenograft mouse model.
Methods: 3×105 U87-Luc cells were stereotactically implanted into the cortex of 35 nude mice and grouped for treatment (n = 7 in each group): IP saline (group 1), single IP BV (group 2), biweekly IP BV for 3 weeks (group 3), single intra-arterial (IA) BV alone (group 4) and single IA BV with blood brain barrier disruption (BBBD) (group 5). Tumor growth was monitored every 3 to 4 days using bioluminescence imaging (BLI) and survival was analyzed by the Kaplan Meier method. Tumor tissue was analyzed using H&E staining and immunohistochemistry.
Results: Based on BLI, BV treated mice showed a delayed tumor growth over time compared to control. Kaplan Meier analysis demonstrated a median survival time of 28 days for group 1, 31 days for group 2, 34 days for group 3, 36 days for group 4 and 36 days for group 5 (p<0.0001). Mice treated with repeated IP BV (p = 0.003) or single IA BV with (p = 0.015) or without (p = 0.005) BBBD showed a significant survival benefit compared to single IP BV treated mice. Post mortem analysis revealed a histological pattern with a more discontinuous border between tumor and mouse brain in the repeated IP BV and single IA BV with or without BBBD treated mice compared to the sharply defined edges of single IP BV treated and control mice.
Conclusions: In this study we showed a significant survival benefit of repeated IP BV and single IA BV with or without BBBD treated mice compared to single IP BV treated and control mice in a U87 xenograft model.
Keywords: Glioblastoma Multiforme, Xenograft Mouse Model, Intra-arterial Chemotherapy, Bevacizumab, U87