skip to main content

Title: Inhibition of Vascular Endothelial Growth Factor A and Hypoxia-Inducible Factor 1α Maximizes the Effects of Radiation in Sarcoma Mouse Models Through Destruction of Tumor Vasculature

Purpose: To examine the addition of genetic or pharmacologic inhibition of hypoxia-inducible factor 1α (HIF-1α) to radiation therapy (RT) and vascular endothelial growth factor A (VEGF-A) inhibition (ie trimodality therapy) for soft-tissue sarcoma. Methods and Materials: Hypoxia-inducible factor 1α was inhibited using short hairpin RNA or low metronomic doses of doxorubicin, which blocks HIF-1α binding to DNA. Trimodality therapy was examined in a mouse xenograft model and a genetically engineered mouse model of sarcoma, as well as in vitro in tumor endothelial cells (ECs) and 4 sarcoma cell lines. Results: In both mouse models, any monotherapy or bimodality therapy resulted in tumor growth beyond 250 mm{sup 3} within the 12-day treatment period, but trimodality therapy with RT, VEGF-A inhibition, and HIF-1α inhibition kept tumors at <250 mm{sup 3} for up to 30 days. Trimodality therapy on tumors reduced HIF-1α activity as measured by expression of nuclear HIF-1α by 87% to 95% compared with RT alone, and cytoplasmic carbonic anhydrase 9 by 79% to 82%. Trimodality therapy also increased EC-specific apoptosis 2- to 4-fold more than RT alone and reduced microvessel density by 75% to 82%. When tumor ECs were treated in vitro with trimodality therapy under hypoxia, there were significant decreases in proliferation and colony formationmore » and increases in DNA damage (as measured by Comet assay and γH2AX expression) and apoptosis (as measured by cleaved caspase 3 expression). Trimodality therapy had much less pronounced effects when 4 sarcoma cell lines were examined in these same assays. Conclusions: Inhibition of HIF-1α is highly effective when combined with RT and VEGF-A inhibition in blocking sarcoma growth by maximizing DNA damage and apoptosis in tumor ECs, leading to loss of tumor vasculature.« less
Authors:
 [1] ;  [2] ;  [3] ;  [3] ;  [2] ;  [4] ;  [1] ;  [1] ;  [2] ;  [5] ;  [4] ;  [6] ;  [7] ;  [8] ;  [4] ;  [8] ;
  1. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States)
  2. (Korea, Republic of)
  3. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
  4. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States)
  5. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
  6. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States)
  7. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (United States)
  8. (United States)
Publication Date:
OSTI Identifier:
22458633
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 91; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANIMAL TISSUES; ANOXIA; APOPTOSIS; CARBONIC ANHYDRASE; COLONY FORMATION; COMPARATIVE EVALUATIONS; DNA; DNA DAMAGES; DOXORUBICIN; GROWTH; GROWTH FACTORS; IN VITRO; INHIBITION; MICE; RADIOTHERAPY; RNA; SARCOMAS