title: Radiation-induced enteropathy: molecular basis of pentoxifylline-vitamin E anti-fibrotic effect involved TGF-β1 cascade inhibition.
abstract: BACKGROUND
  Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline-vitamin E has proven effective and safe in clinical trials in the treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored.
  
  
  METHODS
  Ten patients suffering from radiation-induced enteropathy were treated with pentoxifylline-vitamin E combination with SOMA score as the primary endpoint. In parallel, primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy were incubated with pentoxifylline, trolox (vit. E hydrophilic analogous) or their combination. Activation of the TGF-β1/Smad and Rho/ROCK pathways was subsequently investigated using Q-RT-PCR, gene reporter, Western-blot, ELISA and immunohistochemistry.
  
  
  RESULTS
  Pentoxifylline-vitamin E combination induces regression of symptoms (SOMA) by -41% and -80% at 6 and 18months. In vitro, pentoxifylline and trolox synergize to inhibit TGF-β1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-β1/Smad targets (Col Iα1, FN1, PAI-1, CTGF), while it has no effect on the Rho/ROCK pathway.
  
  
  CONCLUSIONS
  The anti-fibrotic effect of combined pentoxifylline-vitamin E is at least in part mediated by inhibition of the TGF-β1 cascade. It strengthens previous clinical data showing pentoxifylline-vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis.
authors.affiliation: Molecular Radiotherapy, Université Paris Sud XI, Le Kremlin Bicêtre, France. saad.hamama@igr.fr
authors.forename: Saad
authors.initials: S
authors.lastname: Hamama
authors.forename: Marie
authors.initials: M
authors.lastname: Gilbert-Sirieix
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Vozenin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Delanian
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D002986:Clinical Trials as Topic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005355:Fibrosis / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D007150:Immunohistochemistry; D007410:Intestinal Diseases / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D010431:Pentoxifylline / Q000494:pharmacology / Q000627:therapeutic use*; D011837:Radiation-Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011878:Radiotherapy / Q000009:adverse effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000187:drug effects*; D016896:Treatment Outcome; D014810:Vitamin E / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D011837:Radiation-Protective Agents; D053773:Transforming Growth Factor beta1; D014810:Vitamin E; D010431:Pentoxifylline