title: Influence of manipulating hypoxia in solid tumors on the radiation dose-rate effect in vivo, with reference to that in the quiescent cell population.
abstract: OBJECTIVE
  The aim of this study was to clarify the effect of manipulating intratumor hypoxia on radiosensitivity under reduced dose-rate (RDR) irradiation.
  
  
  METHODS
  Tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. They received gamma-rays or accelerated carbon-ion beams at high dose-rate (HDR) or RDR with or without tumor clamping to induce hypoxia. Some mice without clamping received nicotinamide, an acute hypoxia-releasing agent or misonidazole, a hypoxic cell radio-sensitizer before irradiation. The responses of quiescent (Q) and total (= P + Q) cells were assessed by the micronucleus frequency using immunofluorescence staining for BrdU.
  
  
  RESULTS
  The clearer decrease in radiosensitivity in Q than total cells after RDR gamma-ray irradiation was suppressed with carbon-ion beams, especially with a higher linear energy transfer value. Repressing the decrease in the radiosensitivity under RDR irradiation through keeping tumors hypoxic during irradiation and enhancing the decrease in the radiosensitivity by nicotinamide were clearer with gamma-rays and in total cells than with carbon-ion beams and in Q cells, respectively. Inhibiting the decrease in the radiosensitivity by misonidazole was clearer with gamma-rays and in Q cells than with carbon-ion beams and in total cells, respectively.
  
  
  CONCLUSIONS
  Manipulating hypoxia during RDR as well as HDR irradiation influences tumor radiosensitivity, especially with gamma-rays.
authors.affiliation: Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Sennan-gun, Osaka, Japan. smasuna@rri.kyoto-u.ac.jp
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Masunaga
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Hirayama
authors.forename: Akiko
authors.initials: A
authors.lastname: Uzawa
authors.forename: Genro
authors.initials: G
authors.lastname: Kashino
authors.forename: Takushi
authors.initials: T
authors.lastname: Takata
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Minoru
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kinashi
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Sachiko
authors.initials: S
authors.lastname: Koike
authors.forename: Koichi
authors.initials: K
authors.lastname: Ando
authors.forename: Koji
authors.initials: K
authors.lastname: Ono
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001973:Bromodeoxyuridine / Q000008:administration & dosage; D002250:Carbon Radioisotopes / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000532:radiotherapy*; D015687:Cell Hypoxia; D002470:Cell Survival / Q000528:radiation effects; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000008:administration & dosage; D009536:Niacinamide / Q000008:administration & dosage; D011836:Radiation Tolerance / Q000528:radiation effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D014803:Vitamin B Complex / Q000008:administration & dosage
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D011838:Radiation-Sensitizing Agents; D014803:Vitamin B Complex; D009536:Niacinamide; D008920:Misonidazole; D001973:Bromodeoxyuridine