title: The usefulness of mild temperature hyperthermia combined with continuous tirapazamine administration under reduced dose-rate irradiation with gamma-rays.
abstract: OBJECTIVE
  We clarified the usefulness of mild temperature hyperthermia (MTH) in combination with the continuous administration of tirapazamine (TPZ) under reduced dose-rate irradiation (RDRI) using gamma-rays.
  
  
  METHODS
  SCC VII tumour-bearing mice received a continuous administration of 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. Then, they received a 24 h continuous subcutaneous infusion of TPZ either with or without MTH under high dose-rate irradiation (HDRI) or RDRI using gamma-rays. After the irradiation, the tumour cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in non-proliferating tumour cells without BrdU labeling (= quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. The MN frequency in the total tumour cell populations was determined using tumours that were not pretreated with BrdU.
  
  
  RESULTS
  The sensitivity of both the total and Q cell populations, especially the latter, was significantly reduced with RDRI compared with HDRI. TPZ increased the sensitivity of both populations, with a slightly more remarkable increase in Q cells. Further, MTH combined with TPZ raised the sensitivity of both the total and Q cell populations, especially the latter, under RDRI more markedly than under HDRI.
  
  
  CONCLUSIONS
  From the viewpoint of solid tumour control as a whole, including intratumour Q-cell control, the use of TPZ, especially in combination with MTH, is useful for suppressing the reduction in the sensitivity of tumour cells caused by the decrease in irradiation dose rate in vivo.
authors.affiliation: Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Osaka, Japan. smasuna@rri.kyoto-u.ac.jp
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Masunaga
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
authors.forename: Kenji
authors.initials: K
authors.lastname: Nagata
authors.forename: Minoru
authors.initials: M
authors.lastname: Suzuki
authors.forename: Genro
authors.initials: G
authors.lastname: Kashino
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kinashi
authors.forename: Koji
authors.initials: K
authors.lastname: Ono
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D005334:Fever; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine