Effect of atorvastatin on 5-fluorouracil-induced experimental oral mucositis.
OBJECTIVE
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.
Medeiros
C A C X
CA
Department of Biomedical Sciences, State University of Rio Grande do Norte, Mossoró, Brazil.
Leitão
R F C
RF
Macedo
R N
RN
Barboza
D R M M
DR
Gomes
A S
AS
Nogueira
N A P
NA
Alencar
N M N
NM
Ribeiro
R A
RA
Brito
G A C
GA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D000069059:Atorvastatin; D016470:Bacteremia / Q000139:chemically induced / Q000382:microbiology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000633:toxicity*; D006538:Heptanoic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008647:Mesocricetus; D009061:Mouth Mucosa / Q000187:drug effects / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D013280:Stomatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009573:Nitrites; D011758:Pyrroles; D013438:Sulfhydryl Compounds; D000069059:Atorvastatin; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D005472:Fluorouracil