Format

Send to

Choose Destination
See comment in PubMed Commons below
PLoS One. 2014 Apr 15;9(4):e93888. doi: 10.1371/journal.pone.0093888. eCollection 2014.

Dll4-notch signalling blockade synergizes combined ultrasound-stimulated microbubble and radiation therapy in human colon cancer xenografts.

Author information

1
Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
2
Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
3
Department of Oncology Research, MedImmune, Maryland, United States of America.

Abstract

Tumour vasculature acts as an essential lifeline for tumour progression and facilitates metastatic spread. Novel vascular targeting strategies aiming to sustain vascular shutdown could potentially induce substantial damage, resulting in a significant tumour growth delay. We investigated the combination of two novel complementary vascular targeting agents with radiation therapy in a strategy aiming to sustain vascular disruption. Experiments were carried out with delta-like ligand 4 (Dll4) blockade (angiogenesis deregulator) treatment administered in combination with a radiation-based vascular destruction treatment in a highly aggressive well-perfused colon cancer tumour line implanted in female athymic nude mice. Tumours were treated with permutations of radiation, ultrasound-stimulated microbubbles (USMB) and Dll4 monoclonal antibody (mAb). Tumour vascular response was assessed with three-dimensional power Doppler ultrasound to measure active flow and immunohistochemistry. Tumour response was assessed with histochemical assays and longitudinal measurements of tumour volume. Our results suggest a significant tumour response in animals treated with USMB combined with radiation, and Dll4 mAb, leading to a synergistic tumour growth delay of up to 24 days. This is likely linked to rapid cell death within the tumour and a sustained tumour vascular shutdown. We conclude that the triple combination treatments cause a vascular shutdown followed by a sustained inhibition of angiogenesis and tumour cell death, leading to a rapid tumour vascular-based 'collapse' and a significant tumour growth delay.

PMID:
24736631
PMCID:
PMC3988033
DOI:
10.1371/journal.pone.0093888
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Support Center