title: Protective Effect of Leuprorelin on Radiation-induced Intestinal Toxicity.
abstract: OBJECTIVE
  Patients with prostate cancer treated with neoadjuvant androgen ablation experience less radiation-induced intestinal toxicity, mostly due to a reduction of the volume of normal tissue exposed to high radiation doses. We aimed to evaluate if the anti-androgenic drug leuprorelin itself exerts a protective effect on irradiated bowel.
  
  
  METHODS
  Female, intact and castrated male C57BL/6J mice underwent 12-Gy total body irradiation, with or without a three-month leuprorelin (0.054 mg/kg/month i.p.) pre-treatment. After 24-72 h, mice were sacrificed and intestinal segments collected for histological, immunohistochemical and molecular analyses.
  
  
  RESULTS
  Leuprorelin markedly reduced radiation-induced jejunal and colonic histological alterations in mice, increased the number of regenerating crypts vs. irradiation, and reduced radiation-induced nitrotyrosine immunoreactivity. Leuprorelin significantly reduced radiation-induced matrix metallo-proteinase-2 (Mmp2) and -13, collagen 1 and -3, transforming growth factor-beta (Tgfb), p53, interleukin 6 (Il6), and B-cell lymphoma 2 (Bcl2)-associated X protein (Bax) gene expressions, and nuclear factor-kappa B (NFκB) and TGFβ protein expression, and hampered radiation-induced BCL2 protein down-regulation.
  
  
  CONCLUSIONS
  Leuprorelin protects mice from radiation-induced intestinal injury, likely through a reduction of tissue oxidative stress. These findings give a biological interpretation to clinical observations of improved intestinal tolerance in patients undergoing androgen ablation before RT.
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy monica.mangoni@unifi.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Mangoni
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Sottili
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gerini
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Fucci
authors.affiliation: Histology and Embryology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.affiliation: Histology and Embryology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Calosi
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Bonomo
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Detti
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Greto
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Icro
authors.initials: I
authors.lastname: Meattini
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Simontacchi
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Loi
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Scartoni
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Furfaro
authors.affiliation: Medical Physics Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pallotta
authors.affiliation: Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Livi
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D016729:Leuprolide / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000378:metabolism; D011837:Radiation-Protective Agents / Q000494:pharmacology*
chemical_list: D011837:Radiation-Protective Agents; D016729:Leuprolide
keywords: Leuprorelin; intestinal injury; radioprotection; radiotherapy