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S-nitrosoglutathione accelerates recovery from 5-fluorouracil-induced oral mucositis.

Skeff MA, Brito GA, de Oliveira MG, Braga CM, Cavalcante MM, Baldim V, Holanda-Afonso RC, Silva-Boghossian CM, Colombo AP, Ribeiro RA, Moura-Neto V, Leitão RF - PLoS ONE (2014)

Bottom Line: 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.HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14.Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.

View Article: PubMed Central - PubMed

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.

ABSTRACT

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-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.

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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Related in: MedlinePlus

TNF-α and IL-1β levels (pg/ml) in the cheek pouches of hamsters subjected to 5-FU-induced oral mucositis on day 14.Oral mucositis was induced in hamsters by intraperitoneal (i.p.) injection of 5-FU followed by mechanical trauma (MT) of the cheek pouch. Animals received topical applications of a gel containing S-nitrosoglutathione (0.1, 0.5 and 2.0 mM HPMC/GSNO) 30 min prior to 5-FU and twice daily thereafter for 10 days or 14 days. Control groups comprised normal animals (N), animals subjected to mechanical trauma (MT) only and animals subjected to 5-FU-induced oral mucositis that received local application of saline (saline) or vehicle (HPMC). Bars denote the mean ± standard error of TNF-α and IL-1β levels in six animals per group. *denotes values significantly different (P<0.05) from the Healthy group; +denotes values significantly different (P<0.05) from the Saline group; #denotes values significantly different (P<0.05) from the HPMC group. Data were analyzed using the Kruskal Wallis and Mann Whitney tests.
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pone-0113378-g003: TNF-α and IL-1β levels (pg/ml) in the cheek pouches of hamsters subjected to 5-FU-induced oral mucositis on day 14.Oral mucositis was induced in hamsters by intraperitoneal (i.p.) injection of 5-FU followed by mechanical trauma (MT) of the cheek pouch. Animals received topical applications of a gel containing S-nitrosoglutathione (0.1, 0.5 and 2.0 mM HPMC/GSNO) 30 min prior to 5-FU and twice daily thereafter for 10 days or 14 days. Control groups comprised normal animals (N), animals subjected to mechanical trauma (MT) only and animals subjected to 5-FU-induced oral mucositis that received local application of saline (saline) or vehicle (HPMC). Bars denote the mean ± standard error of TNF-α and IL-1β levels in six animals per group. *denotes values significantly different (P<0.05) from the Healthy group; +denotes values significantly different (P<0.05) from the Saline group; #denotes values significantly different (P<0.05) from the HPMC group. Data were analyzed using the Kruskal Wallis and Mann Whitney tests.

Mentions: 5-FU significantly (P<0.05) increased cheek pouch tissue levels of TNF-α but not IL-1β on day 14 (Figures 3A and 3B). The topical application 0.5 mM HPMC/GSNO but not 0.1 mM or 2.0 mM HPMC/GSNO reduced the 5-FU-induced increase in TNF-α and restored this parameter to the levels of Healthy or MT control animals (Figure 3A). No significant differences in IL-1 levels were observed between experimental groups on day 14 (Figure 3B).


S-nitrosoglutathione accelerates recovery from 5-fluorouracil-induced oral mucositis.

Skeff MA, Brito GA, de Oliveira MG, Braga CM, Cavalcante MM, Baldim V, Holanda-Afonso RC, Silva-Boghossian CM, Colombo AP, Ribeiro RA, Moura-Neto V, Leitão RF - PLoS ONE (2014)

TNF-α and IL-1β levels (pg/ml) in the cheek pouches of hamsters subjected to 5-FU-induced oral mucositis on day 14.Oral mucositis was induced in hamsters by intraperitoneal (i.p.) injection of 5-FU followed by mechanical trauma (MT) of the cheek pouch. Animals received topical applications of a gel containing S-nitrosoglutathione (0.1, 0.5 and 2.0 mM HPMC/GSNO) 30 min prior to 5-FU and twice daily thereafter for 10 days or 14 days. Control groups comprised normal animals (N), animals subjected to mechanical trauma (MT) only and animals subjected to 5-FU-induced oral mucositis that received local application of saline (saline) or vehicle (HPMC). Bars denote the mean ± standard error of TNF-α and IL-1β levels in six animals per group. *denotes values significantly different (P<0.05) from the Healthy group; +denotes values significantly different (P<0.05) from the Saline group; #denotes values significantly different (P<0.05) from the HPMC group. Data were analyzed using the Kruskal Wallis and Mann Whitney tests.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4257535&req=5

pone-0113378-g003: TNF-α and IL-1β levels (pg/ml) in the cheek pouches of hamsters subjected to 5-FU-induced oral mucositis on day 14.Oral mucositis was induced in hamsters by intraperitoneal (i.p.) injection of 5-FU followed by mechanical trauma (MT) of the cheek pouch. Animals received topical applications of a gel containing S-nitrosoglutathione (0.1, 0.5 and 2.0 mM HPMC/GSNO) 30 min prior to 5-FU and twice daily thereafter for 10 days or 14 days. Control groups comprised normal animals (N), animals subjected to mechanical trauma (MT) only and animals subjected to 5-FU-induced oral mucositis that received local application of saline (saline) or vehicle (HPMC). Bars denote the mean ± standard error of TNF-α and IL-1β levels in six animals per group. *denotes values significantly different (P<0.05) from the Healthy group; +denotes values significantly different (P<0.05) from the Saline group; #denotes values significantly different (P<0.05) from the HPMC group. Data were analyzed using the Kruskal Wallis and Mann Whitney tests.
Mentions: 5-FU significantly (P<0.05) increased cheek pouch tissue levels of TNF-α but not IL-1β on day 14 (Figures 3A and 3B). The topical application 0.5 mM HPMC/GSNO but not 0.1 mM or 2.0 mM HPMC/GSNO reduced the 5-FU-induced increase in TNF-α and restored this parameter to the levels of Healthy or MT control animals (Figure 3A). No significant differences in IL-1 levels were observed between experimental groups on day 14 (Figure 3B).

Bottom Line: 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.HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14.Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.

View Article: PubMed Central - PubMed

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.

ABSTRACT

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-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.

Conclusion: Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.

Show MeSH
Related in: MedlinePlus