Journal
PLOS ONE
Volume 9, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0113378
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Funding
- Brazilian Federal Agency for the Support and Evaluation of Graduate Education (DINTER UFC-UFRJ/CAPES)
- National Council for Scientific and Technological Development (CNPq)
- Nacional Institute of Biomedicine of Brazilian Semiarid (IBISAB)
- National Institute for Translational Neuroscience (INNT)
- Rio de Janeiro State Research Foundation (FAPERJ)
- Sao Paulo Research Foundation (FAPESP)
- PhD Program on Morphological Sciences (PMC) from the Federal University of Rio de Janeiro (UFRJ)
- Frauzino Foundation to Cancer Research
- CNPq [309390/2011-7, 478380/2011-9]
- FAPESP [2008/57560-0]
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Introduction: Mucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side-effect of cancer therapy. Aim: 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. Materials and 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-alpha and IL-1 beta levels, immunohistochemical staining for iNOS, TNF-alpha, IL-1 beta, Ki67 and TGF-beta 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. Conclusion: Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.
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