title: Radiosensitizing properties of bortezomib depend on therapeutic schedule.
abstract: OBJECTIVE
  To investigate the influence of the bortezomib (BTZ) on malignant glioma radiosensitivity in two xenograft models.
  
  
  METHODS
  For TCG3 and U87 models, we evaluated the antitumor activity of BTZ, radiotherapy, and BTZ plus radiothearapy according to two therapeutic schedules: a "nonfractionated" schedule corresponding to a single dose of treatment per week, and a "fractionated" schedule corresponding to the same weekly dose divided into 5 fractions. Treatments influence on proliferation and apoptosis indexes, cell cycle distribution, and nuclear factor-κB pathway were explored.
  
  
  RESULTS
  The radiosensitizing properties of BTZ observed with the nonfractionated schedule were lost with the fractionated schedule. Bortezomib-mediated radiosensitization was associated with an increased apoptosis response and major changes in cell proliferation, but the nuclear factor-κB pathway was not involved. Most of the cellular effects induced by BTZ when tumors received a single irradiation were cancelled out if radiotherapy was fractionated.
  
  
  CONCLUSIONS
  The influence of BTZ on glioma radiosensitivity seems to depend on the treatment fractionation schedule, emphasizing the need to clarify the mechanisms underlying BTZ's radiosensitizing effects before further clinical trials are initiated.
authors.affiliation: EA 4421 SiGReTO, UHP Nancy-University, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Labussière
authors.forename: Sophie
authors.initials: S
authors.lastname: Pinel
authors.forename: Marc
authors.initials: M
authors.lastname: Vandamme
authors.forename: François
authors.initials: F
authors.lastname: Plénat
authors.forename: Pascal
authors.initials: P
authors.lastname: Chastagner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D011838:Radiation-Sensitizing Agents; D000069286:Bortezomib