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Amifostine and glutathione prevent ifosfamide- and acrolein-induced hemorrhagic cystitis

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Abstract

Introduction: Ifosfamide (IFS) is an antineoplastic alkylating agent whose major side effect is hemorrhagic cystitis (HC). This toxicity is attributed to the renal excretion of acrolein (ACR), a highly urotoxic IFS metabolite. Despite the clinical use of mesna to prevent HC, a significant percent (∼33%) of patients present with at last one feature of HC, mainly hematuria. Aim: To investigate the use of two antioxidants—amifostine and glutathione—for the prevention of experimental IFS- and ACR-induced HC. Materials and methods: Male Swiss mice were treated intraperitoneal (i.p.) with saline (control), glutathione (125, 250 or 500 mg/kg) or amifostine (25, 50 or 100 mg/kg), and 30 min later they received a single i.p. injection of IFS at a dose of 400 mg/kg. To investigate the systemic effects of the antioxidants on ACR-induced HC, the animals were treated with saline, amifostine (50 mg/kg, i.p.) or glutathione (500 mg/kg, i.p.), and 30 min afterward with 75 μg ACR intravesically (i.ve.). In another set of experiments, the antioxidants were injected directly into the bladder, where the mice received a single i.ve injection of ACR (75 μg) plus amifostine (1.5 mg/kg) or glutathione (2 mg/kg). HC was measured 3 h after IFS or ACR injection according to bladder wet weight, macroscopic (edema and hemorrhage) and microscopic changes, i.e., edema, hemorrhage, cellular infiltration, fibrin deposition and urothelial desquamation. Results: Pretreatments with amifostine or glutathione prevented IFS-induced HC in a dose-dependent manner. Furthermore, ACR-induced HC was also prevented by systemic (i.p.) or local (i.ve.) pretreatment with glutathione or amifostine. The greatest protective effect was seen with local amifostine treatment (2 mg/kg i.ve.) (P < 0.05). Conclusions: Glutathione and amifostine show a beneficial effect in experimental IFS- and ACR-induced HC. Thus, they should be investigated as an alternative treatment to prevent HC observed in patients undergoing IFS treatment.

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Acknowledgements

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). We are grateful for the technical assistance of Maria Silvandira Freire and José Ivan Rodrigues from the Federal University of Ceará. We also thank Dr. A. Leyva for English language editing of the manuscript.

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Authors and Affiliations

  1. Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Hospital do Câncer—Instituto do Câncer do Ceará and Universidade Federal do Ceará, Rua Coronel Nunes de Melo, 1127, Rodolfo Teófilo, 60430-270, Fortaleza, CE, Brazil

    R. A. Ribeiro

  2. Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Rua Coronel Nunes de Melo, 1127, Rodolfo Teófilo, 60430-270, Fortaleza, CE, Brazil

    C. K. L. P. Batista, J. M. S. C. Mota, M. L. P. Souza, B. T. A. Leitão & M. H. L. P. Souza

  3. Departamento de Morfologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brazil

    G. A. C. Brito

  4. Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil

    F. Q. Cunha

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  1. C. K. L. P. Batista
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  2. J. M. S. C. Mota
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  3. M. L. P. Souza
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  4. B. T. A. Leitão
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  5. M. H. L. P. Souza
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  6. G. A. C. Brito
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  7. F. Q. Cunha
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  8. R. A. Ribeiro
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Correspondence to R. A. Ribeiro.

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Batista, C.K.L.P., Mota, J.M.S.C., Souza, M.L.P. et al. Amifostine and glutathione prevent ifosfamide- and acrolein-induced hemorrhagic cystitis. Cancer Chemother Pharmacol 59, 71–77 (2007). https://doi.org/10.1007/s00280-006-0248-z

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  • DOI: https://doi.org/10.1007/s00280-006-0248-z

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