5-Fluorouracil induces inflammation and oxidative stress in the major salivary glands affecting salivary flow and saliva composition.

This study aimed to elucidate the effect of 5-fluorouracil (5-FU) on the histological aspects of the major salivary glands, salivary flow and saliva composition using an established oral mucositis model in hamsters. Oral mucositis was induced by two intraperitoneal administrations of 5-FU in two consecutive days (60 and 40mg/kg), followed by cheek pouch mucosa scratch, on day 4. The Pilocarpine-stimulated salivary flow was measured 4 and 10days after the first 5-FU injection. Salivary glands were harvested for histopathological analysis, measurement of inflammatory cells, quantification of pro-inflammatory cytokines (TNF-α and IL-1ß), investigation of cell death and cell proliferation. Oxidative stress and oxidative defense system were also investigated in the salivary gland tissues using MDA (malondialdehyde), nitrite, non-protein sulfhydryl groups (NP-SH), SOD (superoxide dismutase) and CAT (catalase). In addition, the CAT and lysozyme activities and the IgA and SOD levels were evaluated in the saliva samples. 5-FU significantly reduced the pilocarpine-stimulated salivary flow rate on the 4th experimental day, associated with an increase in the SOD levels in saliva. Recovery of the salivary flow and SOD were observed on day 10, when an increase in the saliva lysozyme levels was detected. In addition, 5-FU promoted vacuolization in parotid (P) and periductal edema in submandibular (SM) gland, combined with an increase in the inflammatory cells influx, mostly observed on the 4th day in SM gland and on 4th and 10th days in P. Oxidative stress was found mostly on day 10 in SM, SL and P glands, associated with release of proinflammatory cytokines, observed in SM and SL glands, but not in P. 5-FU induces an inflammatory response in the major salivary glands, most observed ten days after its first injection, which may contribute to the major salivary glands hypofunction, leading to alterations in the salivary flow rate and composition.

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

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-1ß levels, immunohistochemical staining for iNOS, TNF-α, IL-1ß, Ki67 and TGF-ß 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.