title: The prospective application of a hypoxic radiosensitizer, doranidazole to rat intracranial glioblastoma with blood brain barrier disruption.
abstract: BACKGROUND
  Glioblastoma is one of the intractable cancers and is highly resistant to ionizing radiation. This radioresistance is partly due to the presence of a hypoxic region which is widely found in advanced malignant gliomas. In the present study, we evaluated the effectiveness of the hypoxic cell sensitizer doranidazole (PR-350) using the C6 rat glioblastoma model, focusing on the status of blood brain barrier (BBB).
  
  
  METHODS
  Reproductive cell death in the rat C6 glioma cell line was determined by means of clonogenic assay. An intracranial C6 glioma model was established for the in vivo experiments. To investigate the status of the BBB in C6 glioma bearing brain, we performed the Evans blue extravasation test. Autoradiography with [(14)C]-doranidazole was performed to examine the distribution of doranidazole in the glioma tumor. T2-weighted MRI was employed to examine the effects of X-irradiation and/or doranidazole on tumor growth.
  
  
  RESULTS
  Doranidazole significantly enhanced radiation-induced reproductive cell death in vitro under hypoxia, but not under normoxia. The BBB in C6-bearing brain was completely disrupted and [(14)C]-doranidazole specifically penetrated the tumor regions. Combined treatment with X-irradiation and doranidazole significantly inhibited the growth of C6 gliomas.
  
  
  CONCLUSIONS
  Our results revealed that BBB disruption in glioma enables BBB-impermeable radiosensitizers to penetrate and distribute in the target region. This study is the first to propose that in malignant glioma the administration of hydrophilic hypoxic radiosensitizers could be a potent strategy for improving the clinical outcome of radiotherapy without side effects.
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18 Nishi 9, Kita-ku, Sapporo, Hokkaido, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yasui
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Asanuma
authors.forename: Junichi
authors.initials: J
authors.lastname: Kino
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamori
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Meike
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagane
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kubota
authors.forename: Mikinori
authors.initials: M
authors.lastname: Kuwabara
authors.forename: Osamu
authors.initials: O
authors.lastname: Inanami
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001932:Brain Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000473:pathology / Q000532:radiotherapy*; D007093:Imidazoles / Q000494:pharmacology*; D011446:Prospective Studies; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats
chemical_list: D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; C106738:doranidazole