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

• Published in: British journal of cancer 2015-06, Vol.113 (1), p.46-56
• Main 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
• Format: Article
• Language: English
• Subjects: 692/1807/244; 692/4028/67/1059/99; 692/4028/67/1798; 692/699/67/1059/485; Activation, Metabolic; Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cancer Research; Combined Modality Therapy; Drug Resistance; Epidemiology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Male; Mice; Mice, Inbred BALB C; Molecular Medicine; Nitroimidazoles - pharmacokinetics; Nitroimidazoles - therapeutic use; Oncology; Phosphoramide Mustards - pharmacokinetics; Phosphoramide Mustards - therapeutic use; Sarcoma - drug therapy; Sarcoma - radiotherapy; Translational Therapeutics; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2015.186

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 1 α (HIF-1 α ) and HIF-1 α 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-1 α 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-1 α activity.