Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas Journal Article


Authors: Yoon, C.; Lee, H. J.; Park, D. J.; Lee, Y. J.; Tap, W. D.; Eisinger-Mathason, T. S. K.; Hart, C. P.; Choy, E.; Simon, M. C.; Yoon, S. S.
Article Title: Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas
Abstract: Human sarcomas with a poor response to vascular endothelial growth factor-A (VEGF-A) inhibition and radiation therapy (RT) have upregulation of hypoxia-inducible factor 1α (HIF-1α) and HIF-1α target genes. This study examines the addition of the hypoxia-activated chemotherapy TH-302 to VEGF-A inhibition and RT (a.k.a. trimodality therapy).Methods:Trimodality therapy was examined in two xenograft models and in vitro in tumour endothelial cells and sarcoma cell lines.Results:In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth. When TH-302 was added, this trimodality therapy completely blocked tumour growth with tumours remaining dormant for over 3 months after cessation of therapy. Trimodality therapy caused 2.6-to 6.2-fold more endothelial cell-specific apoptosis than bimodality therapies, and microvessel density and HIF-1α activity were reduced to 11-13% and 13-20% of control, respectively. When trimodality therapy was examined in vitro, increases in DNA damage and apoptosis were much more pronounced in tumour endothelial cells compared with that in sarcoma cells, especially under hypoxia.Conclusions:The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1α activity. © 2015 Cancer Research UK. All rights reserved.
Keywords: cancer chemotherapy; controlled study; human cell; cancer growth; drug efficacy; multimodality cancer therapy; nonhuman; cancer radiotherapy; mouse; animal tissue; dna damage; apoptosis; radiation; animal experiment; animal model; in vitro study; tumor xenograft; drug effect; sarcoma; hypoxia; endothelium cell; vasculotropin a; cell hypoxia; hypoxia inducible factor 1alpha; capillary density; vegf-a; human; male; priority journal; article; evofosfamide; sarcoma cell line
Journal Title: British Journal of Cancer
Volume: 113
Issue: 1
ISSN: 0007-0920
Publisher: Nature Publishing Group  
Date Published: 2015-06-30
Start Page: 46
End Page: 56
Language: English
DOI: 10.1038/bjc.2015.186
PROVIDER: scopus
PUBMED: 26010414
PMCID: PMC4647529
DOI/URL:
Notes: Export Date: 3 August 2015 -- Source: Scopus
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MSK Authors
  1. Sam Yoon
    75 Yoon
  2. William Douglas Tap
    188 Tap
  3. Do Joong Park
    16 Park
  4. Changhwan Yoon
    35 Yoon