title: The role of nitric oxide radicals in removal of hyper-radiosensitivity by priming irradiation.
abstract: In this study, a mechanism in which low-dose hyper-radiosensitivity (HRS) is permanently removed, induced by low-dose-rate (LDR) (0.2-0.3 Gy/h for 1 h) but not by high-dose-rate priming (0.3 Gy at 40 Gy/h) was investigated. One HRS-negative cell line (NHIK 3025) and two HRS-positive cell lines (T-47D, T98G) were used. The effects of different pretreatments on HRS were investigated using the colony assay. Cell-based ELISA was used to measure nitric oxide synthase (NOS) levels, and microarray analysis to compare gene expression in primed and unprimed cells. The data show how permanent removal of HRS, previously found to be induced by LDR priming irradiation, can also be induced by addition of nitric oxide (NO)-donor DEANO combined with either high-dose-rate priming or exposure to prolonged cycling hypoxia followed by reoxygenation, a treatment not involving radiation. The removal of HRS appears not to involve DNA damage induced during priming irradiation as it was also induced by LDR irradiation of cell-conditioned medium without cells present. The permanent removal of HRS in LDR-primed cells was reversed by treatment with inducible nitric oxide synthase (iNOS) inhibitor 1400W. Furthermore, 1400W could also induce HRS in an HRS-negative cell line. The data suggest that LDR irradiation for 1 h, but not 15 min, activates iNOS, and also that sustained iNOS activation is necessary for the permanent removal of HRS by LDR priming. The data indicate that nitric oxide production is involved in the regulatory processes determining cellular responses to low-dose-rate irradiation.
authors.affiliation: Department of Physics, University of Oslo, 0316 Oslo, Norway.
authors.forename: Nina Jeppesen
authors.initials: NJ
authors.lastname: Edin
authors.forename: Joe Alexander
authors.initials: JA
authors.lastname: Sandvik
authors.forename: Hilde Synnøve
authors.initials: HS
authors.lastname: Vollan
authors.forename: Katharina
authors.initials: K
authors.lastname: Reger
authors.forename: Agnes
authors.initials: A
authors.lastname: Görlach
authors.forename: Erik Olai
authors.initials: EO
authors.lastname: Pettersen
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology* / Q000528:radiation effects*; D045744:Cell Line, Tumor; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000502:physiology* / Q000528:radiation effects*
chemical_list: D005609:Free Radicals; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: hyper-radiosensitivity; inducible nitric oxide synthase; low dose-rate; nitric oxide