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Title: Radiation-induced nitric oxide mitigates tumor hypoxia and radioresistance in a murine SCCVII tumor model

Highlights: •IR-induced NO increased tissue perfusion and pO{sub 2}. •IR increased NO production in tumors without changes in the mRNA and protein levels of NOS isoforms. •NOS activity assay showed that IR upregulated eNOS activity in tumors. •IR-induced NO decreased tumor hypoxia and altered tumor radiosensitivity. -- Abstract: Tumor hypoxia, which occurs mainly as a result of inadequate tissue perfusion in solid tumors, is a well-known challenge for successful radiotherapy. Recent evidence suggests that ionizing radiation (IR) upregulates nitric oxide (NO) production and that IR-induced NO has the potential to increase intratumoral circulation. However, the kinetics of NO production and the responsible isoforms for NO synthase in tumors exposed to IR remain unclear. In this study, we aimed to elucidate the mechanism by which IR stimulates NO production in tumors and the effect of IR-induced NO on tumor radiosensitivity. Hoechst33342 perfusion assay and electron spin resonance oxymetry showed that IR increased tissue perfusion and pO{sub 2} in tumor tissue. Immunohistochemical analysis using two different hypoxic probes showed that IR decreased hypoxic regions in tumors; treatment with a nitric oxide synthase (NOS) inhibitor, L-NAME, abrogated the effects of IR. Moreover, IR increased endothelial NOS (eNOS) activity without affecting its mRNA ormore » protein expression levels in SCCVII-transplanted tumors. Tumor growth delay assay showed that L-NAME decreased the anti-tumor effect of fractionated radiation (10 Gy × 2). These results suggested that IR increased eNOS activity and subsequent tissue perfusion in tumors. Increases in intratumoral circulation simultaneously decreased tumor hypoxia. As a result, IR-induced NO increased tumor radiosensitivity. Our study provides a new insight into the NO-dependent mechanism for efficient fractionated radiotherapy.« less
Authors:
 [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7] ;  [1]
  1. Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo (Japan)
  2. Department of Tracer Kinetics and Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo (Japan)
  3. Central Institute of Isotope Science, Hokkaido University, Sapporo (Japan)
  4. Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo (Japan)
  5. Food Safety Division, National Food Research Institute, Tsukuba (Japan)
  6. Department of Chemistry, Hokkaido University of Education, Hakodate (Japan)
  7. Center for Medical Education, Sapporo Medical University, Sapporo (Japan)
Publication Date:
OSTI Identifier:
22239687
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 437; Journal Issue: 3; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; ANOXIA; ARGININE; ELECTRON SPIN RESONANCE; ESTERS; IONIZING RADIATIONS; MESSENGER-RNA; NEOPLASMS; NITRIC OXIDE; PARTIAL PRESSURE; PROTEINS; RADIOSENSITIVITY; RADIOTHERAPY