TY - JOUR
AU - Muschel, Ruth J.
AB - BackgroundThe microenvironment plays an important role in regulating tumor response to radiotherapy. Ionizing radiation can disrupt tumor vasculature, and Notch pathway inhibition can interfere with functional angiogenesis. We explored the potential cooperativity between Notch inhibition and ionizing radiation in delaying tumor growth.MethodsHuman colorectal carcinoma LS174T cells, which express the Notch ligand delta-like ligand 4 (DLL4), and human head and neck cancer FaDu cells, which do not, were grown as subcutaneous xenografts in nude mice. The mice were treated with dibenzazepine (DBZ), a -secretase inhibitor that blocks all Notch signaling, or a DLL4-specific blocking monoclonal antibody, alone or in combination with ionizing radiation (n  510 mice per group), and response was assessed by tumor growth delay. Microbubble contrast Doppler ultrasound was used to measure tumor blood flow. Tumor Notch activity was monitored by in vivo bioluminescence from a Notch luciferase reporter. Vessel density was assessed using Chalkley vessel counting. All statistical tests were two-sided.ResultsIn LS174T xenografts, the average time for tumor volumes to reach four times the starting volume was longer for mice treated with the DLL4 monoclonal antibody than for mice treated with DBZ (16.4 vs 9.5 days, difference  6.9 days, 95% confidence interval [CI]  3.7 to 10.1 days, P < .001). Both Notch inhibitors suppressed tumor Notch activity within 24 hours of administration compared with vehicle (change in luciferase activity, vehicle vs DBZ: 103% vs 28%, difference  75%, 95% CI  39% to 109%, P  .002; vehicle vs DLL4 antibody: 172% vs 26%, difference  146%, 95% CI  86% to 205%, P < .001). Administration of the DLL4 antibody or DBZ after ionizing radiation resulted in a supra-additive growth delay compared with vehicle (vehicle vs DLL4 antibody  ionizing radiation: 6.8 vs 44.3 days, difference  37.5 days, 95% CI  32 to 43 days, P < .001; vehicle vs DBZ  ionizing radiation: 7.1 vs 24.4 days, difference  17.3 days, 95% CI  15.9 to 18.6 days, P < .001). Treatment of mice with the DLL4 antibody alone or in combination with ionizing radiation increased tumor vessel density but reduced tumor blood flow. Combination therapy with DLL4 antibody and ionizing radiation resulted in extensive tumor necrosis in LS174T xenografts and enhanced tumor growth delay in FaDu xenografts.ConclusionThe combination of specific DLL4Notch blockade and ionizing radiation impairs tumor growth by promoting nonfunctional tumor angiogenesis and extensive tumor necrosis, independent of tumor DLL4 expression.
TI - Delta-Like Ligand 4Notch Blockade and Tumor Radiation Response
JF - JNCI: Journal of the National Cancer Institute
DO - 10.1093/jnci/djr419
DA - 2011-12-07
UR - https://www.deepdyve.com/lp/oxford-university-press/delta-like-ligand-4notch-blockade-and-tumor-radiation-response-CHHdpBhqbW
SP - 1778
EP - 1798
VL - 103
IS - 23
DP - DeepDyve
ER -