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

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 ( approximately 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 mug 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 mug) 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.

• Authors: C K L P Batista, J M S C Mota, M L P Souza, B T A Leitão, M H L P Souza, G A C Brito, F Q Cunha, R A Ribeiro
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 59 Issue 1 Pg. 71-7 (Jan 2007) ISSN: 0344-5704 [Print] Germany
• PMID: 16708234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antidotes
• Antineoplastic Agents, Alkylating
• Radiation-Protective Agents
• Acrolein
• Glutathione
• Amifostine
• Ifosfamide

Topics

• Acrolein (antagonists & inhibitors, toxicity)
• Amifostine (therapeutic use)
• Animals
• Antidotes (therapeutic use)
• Antineoplastic Agents, Alkylating (antagonists & inhibitors, toxicity)
• Cystitis (chemically induced, pathology, prevention & control)
• Dose-Response Relationship, Drug
• Edema (chemically induced, pathology, prevention & control)
• Glutathione (therapeutic use)
• Hemorrhage (chemically induced, pathology, prevention & control)
• Ifosfamide (antagonists & inhibitors, toxicity)
• Injections, Intraperitoneal
• Injections, Intravenous
• Male
• Mice
• Radiation-Protective Agents (therapeutic use)
• Urinary Bladder (pathology)