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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