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

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Title: Radiation-induced nitric oxide mitigates tumor hypoxia and radioresistance in a murine SCCVII tumor model
Authors: Nagane, Masaki Browse this author
Yasui, Hironobu Browse this author →KAKEN DB
Yamamori, Tohru Browse this author →KAKEN DB
Zhao, Songji Browse this author →KAKEN DB
Kuge, Yuji Browse this author →KAKEN DB
Tamaki, Nagara Browse this author →KAKEN DB
Kameya, Hiromi Browse this author
Nakamura, Hideo Browse this author →KAKEN DB
Fujii, Hirotada Browse this author →KAKEN DB
Inanami, Osamu Browse this author →KAKEN DB
Keywords: Ionizing radiation
Tumor reoxygenation
Electron spin resonance
Nitric oxide
Issue Date: 2-Aug-2013
Publisher: Elsevier
Journal Title: Biochemical and biophysical research communications
Volume: 437
Issue: 3
Start Page: 420
End Page: 425
Publisher DOI: 10.1016/j.bbrc.2013.06.093
PMID: 23831468
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(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 or 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 x 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. (C) 2013 Elsevier Inc. All rights reserved.
Type: article (author version)
Appears in Collections:獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 稲波 修

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