Role of nitric oxide on pathogenesis of 5-fluorouracil induced experimental oral mucositis in hamster.
BACKGROUND
Mucositis induced by antineoplastic drugs is an important, dose-limiting, and costly side effect of cancer therapy.


OBJECTIVE
To investigate the role of nitric oxide (NO) on the pathogenesis of 5-fluorouracil (5-FU)-induced oral mucositis.


METHODS
Oral mucositis was induced by two intraperitoneal (i.p) administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) in male hamsters. Animals were treated subcutaneously with saline (0.4 ml), 1,400 W (1 mg/kg), aminoguanidine (5 or 10 mg/kg) or Nphi-Nitro-L-Arginine Methyl Ester (L-NAME) (5, 10, or 20 mg/kg) 1 h before the injections of 5-FU and daily until sacrifice, on the tenth day. Macroscopic and histopathological analyses were evaluated and graded. Tissues from the cheek pouches were harvested for measurement of myeloperoxidase (MPO) activity, nitrite level, and immunohistochemistry for induced nitric oxide synthase (iNOS).


RESULTS
Treatment with 1,400 W or aminoguanidine reduced macroscopic and histological parameters of oral mucositis, and reduced the inflammatory cell infiltration as detected by histopathology and by MPO activity. In contrast, the administration of L-NAME did not significantly reverse the inflammatory alterations induced by experimental mucositis. Increased NOS activity, nitrite level and immunostaining for iNOS were detected on the check pouch tissue of animals submitted to 5-FU-induced oral mucositis on the tenth day.


CONCLUSIONS
These results suggest an important role of NO produced by iNOS in the pathogenesis of oral mucositis induced by 5-FU.
Leitão
R F C
RF
Departamento de Fisiologia e Farmacologia, Faculdade de Medicina da Universidade Federal do Ceará, Rua Cel Nunes de Melo, 1127, 60.430-270 Fortaleza, CE, Brazil.
Ribeiro
R A
RA
Bellaguarda
E A L
EA
Macedo
F D B
FD
Silva
L R
LR
Oriá
R B
RB
Vale
M L
ML
Cunha
F Q
FQ
Brito
G A C
GA
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000633:toxicity*; D006146:Guanidines / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008647:Mesocricetus; D009061:Mouth Mucosa / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009195:Peroxidase / Q000378:metabolism; D013280:Stomatitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D009195:Peroxidase; D019001:Nitric Oxide Synthase; C004479:pimagedine; D005472:Fluorouracil; D019331:NG-Nitroarginine Methyl Ester