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Role of nitric oxide on pathogenesis of 5-fluorouracil induced experimental oral mucositis in hamster

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Abstract

Introduction

Mucositis induced by antineoplastic drugs is an important, dose-limiting, and costly side effect of cancer therapy. Aim: To investigate the role of nitric oxide (NO) on the pathogenesis of 5-fluorouracil (5-FU)-induced oral mucositis.

Materials and 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 Nϕ-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.

Conclusion

These results suggest an important role of NO produced by iNOS in the pathogenesis of oral mucositis induced by 5-FU.

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Acknowledgments

The authors thank Maria Silvandira França Pinheiro, Department of Physiology and Pharmacology, and José Ivan Rodrigues de Sousa, Department of Morphology, Faculty of Medicine, Federal University of Ceará, Brazil, and Fabiola Leslie A. C. Mestriner, Department of Pharmacology, Faculty of Medicine, Ribeirão Preto, SP, Brazil for technical assistance. This work was supported by the Brazilian Agency for Scientific and Technological Development (CNPq; grant 403676/2004–2005) and Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP; grant 737/03).

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Authors and Affiliations

  1. 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

    R. F. C. Leitão, R. A. Ribeiro, E. A. L. Bellaguarda, F. D. B. Macedo, L. R. Silva & M. L. Vale

  2. Department of Morphology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil

    R. B. Oriá & G. A. C. Brito

  3. Department of Pharmacology, Faculty of Medicine, University of Sao Paulo, Ribeirão Preto, SP, Brazil

    F. Q. Cunha

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  1. R. F. C. Leitão
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Leitão, R.F.C., Ribeiro, R.A., Bellaguarda, E.A.L. et al. Role of nitric oxide on pathogenesis of 5-fluorouracil induced experimental oral mucositis in hamster. Cancer Chemother Pharmacol 59, 603–612 (2007). https://doi.org/10.1007/s00280-006-0301-y

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