Abstract | BACKGROUND: 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.
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Authors | C Yoon, H-J Lee, D J Park, Y-J Lee, W D Tap, T S K Eisinger-Mathason, C P Hart, E Choy, M C Simon, S S Yoon |
Journal | British journal of cancer
(Br J Cancer)
Vol. 113
Issue 1
Pg. 46-56
(Jun 30 2015)
ISSN: 1532-1827 [Electronic] England |
PMID | 26010414
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- HIF1A protein, human
- Hypoxia-Inducible Factor 1, alpha Subunit
- Nitroimidazoles
- Phosphoramide Mustards
- TH 302
- Vascular Endothelial Growth Factor A
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Topics |
- Activation, Metabolic
- Animals
- Antineoplastic Agents
(pharmacokinetics, therapeutic use)
- Combined Modality Therapy
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(physiology)
- Male
- Mice
- Mice, Inbred BALB C
- Nitroimidazoles
(pharmacokinetics, therapeutic use)
- Phosphoramide Mustards
(pharmacokinetics, therapeutic use)
- Sarcoma
(drug therapy, radiotherapy)
- Vascular Endothelial Growth Factor A
(antagonists & inhibitors)
- Xenograft Model Antitumor Assays
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