title: Distribution and radiosensitizing effect of cholesterol-coupled Dbait molecule in rat model of glioblastoma.
abstract: BACKGROUND
  Glioma is the most aggressive tumor of the brain and the most efficient treatments are based on radiotherapy. However, tumors are often resistant to radiotherapy due to an enhanced DNA repair activity. Short and stabilized DNA molecules (Dbait) have recently been proposed as an efficient strategy to inhibit DNA repair in tumor.
  
  
  RESULTS
  The distribution of three formulations of Dbait, (i) Dbait alone, (ii) Dbait associated with polyethylenimine, and (iii) Dbait linked with cholesterol (coDbait), was evaluated one day after intratumoral delivery in an RG2 rat glioma model. Dbait molecule distribution was assessed in the whole organ with 2D-FRI and in brain sections. CoDbait was chosen for further studies given its good retention in the brain, cellular localization, and efficacy in inducing the activation of DNA repair effectors. The radiosensitizing effect of coDbait was studied in four groups of rats bearing RG2-glioma: no treatment, radiotherapy only, coDbait alone, and CoDbait with radiotherapy. Treatment started 7 days after tumor inoculation and consisted of two series of treatment in two weeks: coDbait injection followed by a selective 6-Gy irradiation of the head. We evaluated the radiosensitizing effect using animal survival, tumor volume, cell proliferation, and vasculature characteristics with multiparametric MRI. CoDbait with radiotherapy improved the survival of rats bearing RG2-glioma by reducing tumor growth and cell proliferation without altering tumor vasculature.
  
  
  CONCLUSIONS
  coDbait is therefore a promising molecular therapy to sensitize glioma to radiotherapy.
authors: Inserm, U836, Grenoble, France. nicolas.coquery@ujf-grenoble.fr
authors: Nicolas
authors: N
authors: Coquery
authors: Nicolas
authors: N
authors: Pannetier
authors: Régine
authors: R
authors: Farion
authors: Aurélie
authors: A
authors: Herbette
authors: Leire
authors: L
authors: Azurmendi
authors: Didier
authors: D
authors: Clarencon
authors: Stéphane
authors: S
authors: Bauge
authors: Véronique
authors: V
authors: Josserand
authors: Claire
authors: C
authors: Rome
authors: Jean-Luc
authors: JL
authors: Coll
authors: Jian-Sheng
authors: JS
authors: Sun
authors: Emmanuel L
authors: EL
authors: Barbier
authors: Marie
authors: M
authors: Dutreix
authors: Chantal C
authors: CC
authors: Remy
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002626:Chemistry, Pharmaceutical; D002784:Cholesterol / Q000378:metabolism*; D004247:DNA / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004195:Disease Models, Animal; D018450:Disease Progression; D005909:Glioblastoma / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D008279:Magnetic Resonance Imaging; D008297:Male; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D009389:Neovascularization, Pathologic; D011094:Polyethyleneimine / Q000737:chemistry; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D016019:Survival Analysis; D059016:Tumor Microenvironment / Q000187:drug effects / Q000528:radiation effects
chemical_list: D011838:Radiation-Sensitizing Agents; D011094:Polyethyleneimine; D004247:DNA; D002784:Cholesterol