Amifostine reduces inflammation and protects against 5-fluorouracil-induced oral mucositis and hyposalivation

Abstract

Oral mucositis (OM) is a common and dose-limiting side effect of cancer treatment, including 5-fluorouracil (5-FU) andradiotherapy. The efficacy of the therapeutic measures to prevent OM is limited and disease prevention is not fully observable.Amifostine is a cytoprotective agent with a described anti-inflammatory potential. It is clinically used to reduce radiotherapy andchemotherapy-associated xerostomia. This study investigated the protective effect of amifostine on an experimental model ofOM. Hamsters were divided into six groups: saline control group (5 mL/kg), mechanical trauma (scratches) of the rightcheek pouch; 5-FU (60 and 40 mg/kg,ip, respectively, administered on days 1 and 2); amifostine (12.5, 25, or 50 mg/kg)+5-FU+scratches. Salivation rate was assessed and the animals were euthanized on day 10 for the analysis of macroscopicand microscopic injury by scores. Tissue samples were harvested for the measurement of neutrophil infiltration and detection ofinflammatory markers by ELISA and immunohistochemistry. 5-FU induced pronounced hyposalivation, which was prevented byamifostine (Po0.05). In addition, 5-FU injection caused pronounced tissue injury accompanied by increased neutrophilaccumulation, tumor necrosis factor-alpha (TNF-a), and interleukin-1 beta (IL-1b) tissue levels, and positive immunostaining forTNF-a, IL-1b, and inducible nitric oxide synthase (iNOS). Interestingly, amifostine prevented the inflammatory reaction andconsequently improved macroscopic and microscopic damage (Po0.05vs5-FU group). Amifostine reduced inflammation andprotected against 5-FU-associated oral mucositis and hyposalivation.