Abstract
IntroductionMucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side-effect of cancer therapy.AimTo 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 MethodsOral 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.ResultsThe 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.ConclusionTopical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.
Highlights
Mucositis induced by anti-neoplastic drugs is an important, doselimiting and costly side-effect of cancer therapy
An extrapolation to longer times allows considering that the biological action of nitric oxide (NO) in topical applications is probably maintained over 12 h, a gradual decrease in the rate of NO release is expected in this period
The cheek pouches of animals subjected to 5-FU-induced oral mucositis showed a significant increase (P,0.05) in TUNEL-positive cells on day 14 when compared with the Healthy control group. 0.5 mM hydroxypropyl methylcellulose (HPMC)/GSNO treatment substantially (P,0.05) reduced the number of TUNEL-positive cells in cheek pouch tissue compared with both the HPMC and Saline groups (Figure 6A)
Summary
Mucositis induced by anti-neoplastic drugs is an important, doselimiting and costly side-effect of cancer therapy. 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. This homeostasis between host defense and commensal bacterial has been thought to be disturbed by the cancer itself, by cancer-related secondary immunodeficiency, or by prophylactic antibacterial agents. This disruption in homeostasis may contribute to the oral mucosa tissue breakdown following chemotherapy [7]. The production of large amounts of NO by iNOS has been show to play a major role in immune reactions and in many inflammatory processes including oral mucositis. Beneficial effects may include antimicrobial activity [11], collagen deposition and keratinocyte proliferation [12,13,14]
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