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[Abstract]

BACKGROUND: 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.British Journal of Cancer advance online publication 26 May 2015 doi:10.1038/bjc.2015.186 www.bjcancer.com.

[Author information]

Yoon C1, Lee HJ2, Park DJ3, Lee YJ2, Tap WD4, Eisinger-Mathason TS5, Hart CP6, Choy E7, Simon MC8, Yoon SS1.

1 Department of Surgery, Memorial Sloan-Kettering Cancer Center, H-1209, 1275 York Avenue, New York, NY 10021, USA.

2 1] Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA [2] Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.

3 1] Department of Surgery, Memorial Sloan-Kettering Cancer Center, H-1209, 1275 York Avenue, New York, NY 10021, USA [2] Department of Surgery, Seoul National University Bundang Hospital, Sungnam, South Korea.

4 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

5 Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

6 Threshold Pharmaceuticals, South San Francisco, CA 94080, USA.

7 Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

8 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA [2] Howard Hughes Medical Institute, Chevy Chase, MD, USA.