title: Redox generation of nitric oxide to radiosensitize hypoxic cells.
abstract: OBJECTIVE
  Previous studies have shown that nitric oxide (NO) delivered from NO donor agents sensitizes hypoxic cells to ionizing radiation. In the present study, nitroxyl (NO-), a potential precursor to endogenous NO production, was evaluated for hypoxic cell radiosensitization, either alone or in combination with electron acceptor agents.
  
  
  METHODS
  Radiation survival curves of Chinese hamster V79 lung fibroblasts under aerobic and hypoxic conditions were assessed by clonogenic assay. Hypoxia induction was achieved by metabolism-mediated oxygen depletion in dense cell suspensions. Cells were treated with NO- produced from the nitroxyl donor Angeli's salt (AS, Na2N2O3, sodium trioxodinitrate), in the absence or presence of electron acceptor agents, ferricyanide, or tempol. NO concentrations resulting from the combination of AS and ferricyanide or tempol were measured under hypoxic conditions using an NO-sensitive electrode.
  
  
  RESULTS
  Treatment of V79 cells under hypoxic conditions with AS alone did not result in radiosensitization; however, the combination of AS with ferricyanide or tempol resulted in significant hypoxic radiosensitization with SERs of 2.5 and 2.1, respectively. Neither AS alone nor AS in combination with ferricyanide or tempol influenced aerobic radiosensitivity. The presence of NO generated under hypoxic conditions from the combination of AS with ferricyanide or tempol was confirmed using an NO-sensitive electrode.
  
  
  CONCLUSIONS
  Combining NO- generated from AS with electron acceptors results in NO generation and substantial hypoxic cell radiosensitization. NO- derived from donor agents or endogenously produced in tumors, combined with electron acceptors, may provide an important strategy for radiosensitizing hypoxic cells and warrants in vivo evaluation.
authors.affiliation: Radiation Biology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: W
authors.initials: W
authors.lastname: DeGraff
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: J A
authors.initials: JA
authors.lastname: Cook
authors.forename: J
authors.initials: J
authors.lastname: Gamson
authors.forename: D
authors.initials: D
authors.lastname: Christodoulou
authors.forename: M
authors.initials: M
authors.lastname: Feelisch
authors.forename: D A
authors.initials: DA
authors.lastname: Wink
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003497:Cyclic N-Oxides / Q000378:metabolism / Q000494:pharmacology*; D005292:Ferricyanides / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013113:Spin Labels
chemical_list: D003497:Cyclic N-Oxides; D005292:Ferricyanides; D009573:Nitrites; D009589:Nitrogen Oxides; D011838:Radiation-Sensitizing Agents; D013113:Spin Labels; C007931:hexacyanoferrate III; C021229:oxyhyponitrite; D009569:Nitric Oxide; C039900:nitroxyl; C001803:tempol