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Inhibition of Vascular Endothelial Growth Factor A and Hypoxia-Inducible Factor 1α Maximizes the Effects of Radiation in Sarcoma Mouse Models Through Destruction of Tumor Vasculature
- Source :
- International Journal of Radiation Oncology*Biology*Physics. 91:621-630
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- Purpose To examine the addition of genetic or pharmacologic inhibition of hypoxia-inducible factor 1α (HIF-1α) to radiation therapy (RT) and vascular endothelial growth factor A (VEGF-A) inhibition (ie trimodality therapy) for soft-tissue sarcoma. Methods and Materials Hypoxia-inducible factor 1α was inhibited using short hairpin RNA or low metronomic doses of doxorubicin, which blocks HIF-1α binding to DNA. Trimodality therapy was examined in a mouse xenograft model and a genetically engineered mouse model of sarcoma, as well as in vitro in tumor endothelial cells (ECs) and 4 sarcoma cell lines. Results In both mouse models, any monotherapy or bimodality therapy resulted in tumor growth beyond 250 mm 3 within the 12-day treatment period, but trimodality therapy with RT, VEGF-A inhibition, and HIF-1α inhibition kept tumors at 3 for up to 30 days. Trimodality therapy on tumors reduced HIF-1α activity as measured by expression of nuclear HIF-1α by 87% to 95% compared with RT alone, and cytoplasmic carbonic anhydrase 9 by 79% to 82%. Trimodality therapy also increased EC-specific apoptosis 2- to 4-fold more than RT alone and reduced microvessel density by 75% to 82%. When tumor ECs were treated in vitro with trimodality therapy under hypoxia, there were significant decreases in proliferation and colony formation and increases in DNA damage (as measured by Comet assay and γH2AX expression) and apoptosis (as measured by cleaved caspase 3 expression). Trimodality therapy had much less pronounced effects when 4 sarcoma cell lines were examined in these same assays. Conclusions Inhibition of HIF-1α is highly effective when combined with RT and VEGF-A inhibition in blocking sarcoma growth by maximizing DNA damage and apoptosis in tumor ECs, leading to loss of tumor vasculature.
- Subjects :
- Vascular Endothelial Growth Factor A
Cancer Research
Pathology
medicine.medical_specialty
DNA damage
medicine.medical_treatment
Mice, Transgenic
Radiation Tolerance
Article
Small hairpin RNA
Mice
Cell Line, Tumor
medicine
Animals
Radiology, Nuclear Medicine and imaging
Doxorubicin
RNA, Small Interfering
Antibiotics, Antineoplastic
Radiation
Neovascularization, Pathologic
Radiotherapy
business.industry
Hypoxia-Inducible Factor 1, alpha Subunit
medicine.disease
Combined Modality Therapy
Radiation therapy
Vascular endothelial growth factor A
Treatment Outcome
Oncology
Hypoxia-inducible factors
Apoptosis
Cancer research
Sarcoma, Experimental
Sarcoma
business
DNA Damage
medicine.drug
Subjects
Details
- ISSN :
- 03603016
- Volume :
- 91
- Database :
- OpenAIRE
- Journal :
- International Journal of Radiation Oncology*Biology*Physics
- Accession number :
- edsair.doi.dedup.....e9eb6ea059b472e1b43835c56cb2dfcf