title: Reducing intratumour acute hypoxia through bevacizumab treatment, referring to the response of quiescent tumour cells and metastatic potential.
abstract: OBJECTIVE
  The aim was to evaluate the influence of bevacizumab on intratumour oxygenation status and lung metastasis following radiotherapy, with specific reference to the response of quiescent (Q) cell populations within irradiated tumours.
  
  
  METHODS
  B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray irradiation following treatment with the acute hypoxia-releasing agent nicotinamide or local mild temperature hyperthermia (MTH) with or without the administration of bevacizumab under aerobic conditions or totally hypoxic conditions, achieved by clamping the proximal end of the tumours. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In the other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation.
  
  
  RESULTS
  3 days after bevacizumab administration, acute hypoxia-rich total cell population in the tumour showed a remarkably enhanced radiosensitivity to γ-rays, and the hypoxic fraction (HF) was reduced, even after MTH treatment. However, the hypoxic fraction was not reduced after nicotinamide treatment. With or without γ-ray irradiation, bevacizumab administration showed some potential to reduce the number of lung metastases as well as nicotinamide treatment.
  
  
  CONCLUSIONS
  Bevacizumab has the potential to reduce perfusion-limited acute hypoxia and some potential to cause a decrease in the number of lung metastases as well as nicotinamide.
authors.affiliation: Particle Radiation Oncology, Research Reactor Institute, Kyoto University, Osaka, Japan. smasuna@rri.kyoto-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Masunaga
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Sakurai
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: N
authors.initials: N
authors.lastname: Kondo
authors.forename: A
authors.initials: A
authors.lastname: Maruhashi
authors.forename: K
authors.initials: K
authors.lastname: Ono
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D015687:Cell Hypoxia / Q000187:drug effects; D003131:Combined Modality Therapy; D005260:Female; D005720:Gamma Rays / Q000627:therapeutic use; D006979:Hyperthermia, Induced; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary* / Q000628:therapy; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab