Effect of atorvastatin on 5-fluorouracil-induced experimental oral mucositis

• Published in: Cancer chemotherapy and pharmacology Vol. 67; no. 5; pp. 1085 - 1100
• Main Authors: Medeiros, C. A. C. X., Leitão, R. F. C., Macedo, R. N., Barboza, D. R. M. M., Gomes, A. S., Nogueira, N. A. P., Alencar, N. M. N., Ribeiro, R. A., Brito, G. A. C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.05.2011; Springer; Springer Nature B.V
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Antimetabolites, Antineoplastic - toxicity; Antineoplastic agents; Atorvastatin Calcium; Bacteremia - chemically induced; Bacteremia - microbiology; Biological and medical sciences; Cancer Research; Chemical and Drug Induced Liver Injury - etiology; Cricetinae; Cytokines - metabolism; Dose-Response Relationship, Drug; Facial bones, jaws, teeth, parodontium: diseases, semeiology; Fluorouracil - toxicity; Heptanoic Acids - adverse effects; Heptanoic Acids - therapeutic use; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Leukopenia - chemically induced; Male; Medical sciences; Medicine; Medicine & Public Health; Mesocricetus; Mouth Mucosa - drug effects; Mouth Mucosa - pathology; Nitric Oxide Synthase Type II - metabolism; Nitrites - metabolism; Non tumoral diseases; Oncology; Original Article; Otorhinolaryngology. Stomatology; Peroxidase - metabolism; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pyrroles - adverse effects; Pyrroles - therapeutic use; Stomatitis - chemically induced; Stomatitis - drug therapy; Stomatitis - pathology; Sulfhydryl Compounds - metabolism; Atorvastatin; Oral mucositis; Statin; 5-Fluorouracil; Antineoplastic agent; Enzyme; Stomatology; Fluoropyrimidine derivatives; Transferases; Enzyme inhibitor; Statin derivative; Thymidylate synthase; Stomatitis; Antimetabolic; Methyltransferases; HMG-CoA reductase inhibitor; Pyrimidine derivatives; Hydroxymethylglutaryl-CoA reductase; Oral cavity disease; Oxidoreductases; Fluorouracil
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-010-1409-7

Purpose Oral mucositis (OM) is a frequent side effect in patients with cancer. We investigate the effect of atorvastatin (ATV), a cholesterol-lowering drug, on OM induced by 5-fluorouracil (5-FU) in hamsters. Methods OM was induced by the i.p. administration of 5-FU, with excoriations of the cheek pouch mucosa. The animals were pretreated with i.p. ATV 1, 5 or 10 mg/kg or vehicle (saline and 5% (vol/vol) ethanol) 30 min before 5-FU injection and daily for 5 or 10 days. Samples of cheek pouches and main organs were removed for histopathological analysis, determination of TNF-α, IL-1β, nitrite, non-protein sulfhydryl group (NP-SH) levels, myeloperoxidase (MPO) assay and immunohistochemistry for induced nitric oxide synthase (iNOS). Blood was collected for a leukogram analysis of biochemical parameters and analysis of bacteremia. Results ATV at doses of 1 and 5 mg/kg reduced mucosal damage and inflammation, as well as the levels of cytokines, nitrite and myeloperoxidase activity on the 5th and 10th day of OM and immunostaining for iNOS on the 5th day of OM.ATV at 1 mg/kg increased cheek pouch NP-SH when compared to 5-FU groups on the 10th day of OM. The association between ATV 5 mg/kg and 5-FU decreased the survival rate, amplified the leukopenia of animals, increased transaminase serum levels and caused liver lesions. We also detected the presence of Gram-negative bacillus in the blood of 100% of the animals treated with ATV 5 mg/kg + 5-FU. Conclusions Atorvastatin prevented mucosal damage and inflammation associated with 5-FU-induced OM, but the association of a higher dose of ATV with 5-FU induced hepatotoxicity and amplified leukopenia.