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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

Macroscopic and microscopic aspects of healthy hamster cheek pouches (a and b) or cheek pouches from animals subjected to 5-fluorouracil (5-FU)-induced oral mucositis and that received topical applications of the vehicle HPMC (c and d) or GSNO (0.5 mM) (e and f) observed on day 14.Oral mucositis was induced by i.p. dministration of 5-fluorouracil followed by mechanical trauma of the cheek pouch. Animals received topical applications of S-nitrosoglutathione (0.5 mM HPMC/GSNO) or vehicle only (HPMC) at 1 h prior to 5-FU and every 12 h thereafter for 14 days. Each cheek pouch was everted and photographed, and samples were removed and processed for hematoxylin and eosin staining (100× magnification). Details: in Figure 2c, macroscopic edema (arrowhead) and vasodilation (dotted line) are shown; in Figure 2d, microscopic edema (larger circled) and severe vasodilation (smaller circled) are shown. Arrow = ulcerations.
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pone-0113378-g002: Macroscopic and microscopic aspects of healthy hamster cheek pouches (a and b) or cheek pouches from animals subjected to 5-fluorouracil (5-FU)-induced oral mucositis and that received topical applications of the vehicle HPMC (c and d) or GSNO (0.5 mM) (e and f) observed on day 14.Oral mucositis was induced by i.p. dministration of 5-fluorouracil followed by mechanical trauma of the cheek pouch. Animals received topical applications of S-nitrosoglutathione (0.5 mM HPMC/GSNO) or vehicle only (HPMC) at 1 h prior to 5-FU and every 12 h thereafter for 14 days. Each cheek pouch was everted and photographed, and samples were removed and processed for hematoxylin and eosin staining (100× magnification). Details: in Figure 2c, macroscopic edema (arrowhead) and vasodilation (dotted line) are shown; in Figure 2d, microscopic edema (larger circled) and severe vasodilation (smaller circled) are shown. Arrow = ulcerations.

Mentions: The i.p. administration of 5-FU followed by mechanical trauma of the cheek pouch caused significant macroscopic lesions (P<0.05), which were observed on day 10. Compared with the control group of healthy animals (Figure 2a; Table 2) or animals subjected to mechanical trauma, only 5-FU and mechanical trauma (Table 2) caused increased erythema, hemorrhage, extensive ulcers and abscesses (Table 2). These effects of 5-FU at day 10 were not inhibited significantly by topical application of HPMC/GSNO at any of the concentrations tested (Table 2). On day 14, treatment with 0.5 mM HPMC/GSNO (Figure 2e; Table 2) significantly (P<0.05) reduced inflammatory alterations when compared with the non-treated group subjected to the experimental mucositis (5-FU administration and mechanical irritation) and that received topical application of HPMC only (Figures 2c; Table 2).


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)

Macroscopic and microscopic aspects of healthy hamster cheek pouches (a and b) or cheek pouches from animals subjected to 5-fluorouracil (5-FU)-induced oral mucositis and that received topical applications of the vehicle HPMC (c and d) or GSNO (0.5 mM) (e and f) observed on day 14.Oral mucositis was induced by i.p. dministration of 5-fluorouracil followed by mechanical trauma of the cheek pouch. Animals received topical applications of S-nitrosoglutathione (0.5 mM HPMC/GSNO) or vehicle only (HPMC) at 1 h prior to 5-FU and every 12 h thereafter for 14 days. Each cheek pouch was everted and photographed, and samples were removed and processed for hematoxylin and eosin staining (100× magnification). Details: in Figure 2c, macroscopic edema (arrowhead) and vasodilation (dotted line) are shown; in Figure 2d, microscopic edema (larger circled) and severe vasodilation (smaller circled) are shown. Arrow = ulcerations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257535&req=5

pone-0113378-g002: Macroscopic and microscopic aspects of healthy hamster cheek pouches (a and b) or cheek pouches from animals subjected to 5-fluorouracil (5-FU)-induced oral mucositis and that received topical applications of the vehicle HPMC (c and d) or GSNO (0.5 mM) (e and f) observed on day 14.Oral mucositis was induced by i.p. dministration of 5-fluorouracil followed by mechanical trauma of the cheek pouch. Animals received topical applications of S-nitrosoglutathione (0.5 mM HPMC/GSNO) or vehicle only (HPMC) at 1 h prior to 5-FU and every 12 h thereafter for 14 days. Each cheek pouch was everted and photographed, and samples were removed and processed for hematoxylin and eosin staining (100× magnification). Details: in Figure 2c, macroscopic edema (arrowhead) and vasodilation (dotted line) are shown; in Figure 2d, microscopic edema (larger circled) and severe vasodilation (smaller circled) are shown. Arrow = ulcerations.
Mentions: The i.p. administration of 5-FU followed by mechanical trauma of the cheek pouch caused significant macroscopic lesions (P<0.05), which were observed on day 10. Compared with the control group of healthy animals (Figure 2a; Table 2) or animals subjected to mechanical trauma, only 5-FU and mechanical trauma (Table 2) caused increased erythema, hemorrhage, extensive ulcers and abscesses (Table 2). These effects of 5-FU at day 10 were not inhibited significantly by topical application of HPMC/GSNO at any of the concentrations tested (Table 2). On day 14, treatment with 0.5 mM HPMC/GSNO (Figure 2e; Table 2) significantly (P<0.05) reduced inflammatory alterations when compared with the non-treated group subjected to the experimental mucositis (5-FU administration and mechanical irritation) and that received topical application of HPMC only (Figures 2c; Table 2).

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