title: S-nitrosoglutathione accelerates recovery from 5-fluorouracil-induced oral mucositis.
abstract: BACKGROUND
  Mucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side-effect of cancer therapy.
  
  
  OBJECTIVE
  To evaluate the effect of the topical application of S-nitrosoglutathione (GSNO), a nitric oxide donor, on 5-fluorouracil (5-FU)-induced oral mucositis in hamsters.
  
  
  METHODS
  Oral mucositis was induced in male hamsters by two intraperitoneal administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) followed by mechanical trauma on the fourth day. Animals received saline, HPMC or HPMC/GSNO (0.1, 0.5 or 2.0 mM) 1 h prior to the 5-FU injection and twice a day for 10 or 14 days. Samples of cheek pouches were harvested for: histopathological analysis, TNF-α and IL-1β levels, immunohistochemical staining for iNOS, TNF-α, IL-1β, Ki67 and TGF-β RII and a TUNEL assay. The presence and levels of 39 bacterial taxa were analyzed using the Checkerboard DNA-DNA hybridization method. The profiles of NO released from the HPMC/GSNO formulations were characterized using chemiluminescence.
  
  
  RESULTS
  The HPMC/GSNO formulations were found to provide sustained release of NO for more than 4 h at concentration-dependent rates of 14 to 80 nmol/mL/h. Treatment with HPMC/GSNO (0.5 mM) significantly reduced mucosal damage, inflammatory alterations and cell death associated with 5-FU-induced oral mucositis on day 14 but not on day 10. HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14. In addition, we observed that the chemotherapy significantly increased the levels and/or prevalence of several bacterial species.
  
  
  CONCLUSIONS
  Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.
authors.affiliation: Laboratory of Cell Morphogenesis, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Maria Adriana
authors.initials: MA
authors.lastname: Skeff
authors.affiliation: Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Gerly A C
authors.initials: GA
authors.lastname: Brito
authors.affiliation: Institute of Chemistry, University of Campinas, UNICAMP, Campinas, SP, Brazil.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: de Oliveira
authors.affiliation: Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Cintia M
authors.initials: CM
authors.lastname: Braga
authors.affiliation: Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Matheus M
authors.initials: MM
authors.lastname: Cavalcante
authors.affiliation: Institute of Chemistry, University of Campinas, UNICAMP, Campinas, SP, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Baldim
authors.affiliation: Laboratory of Cell Morphogenesis, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Rosenilde C
authors.initials: RC
authors.lastname: Holanda-Afonso
authors.affiliation: Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Faculty of Dentistry, University of Grande Rio, Duque de Caxias, RJ, Brazil.
authors.forename: Carina M
authors.initials: CM
authors.lastname: Silva-Boghossian
authors.affiliation: Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Colombo
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Ronaldo A
authors.initials: RA
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Cell Morphogenesis, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, RJ, Brazil.
authors.forename: Vivaldo
authors.initials: V
authors.lastname: Moura-Neto
authors.affiliation: Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Renata F C
authors.initials: RF
authors.lastname: Leitão
mesh_terms: D000287:Administration, Topical; D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000009:adverse effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D026422:S-Nitrosoglutathione / Q000008:administration & dosage*; D013280:Stomatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053583:Interleukin-1beta; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D026422:S-Nitrosoglutathione; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D005472:Fluorouracil