Abstract
PURPOSE: Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). In this study, we investigated the participation of cyclooxygenase-2 (COX-2) upon ifosfamide-induced HC. METHODS: Male Wistar rats (150-200 g; six rats per group) were treated with saline, IFS (400 mg/kg, i.p.) and analyzed by changes in bladder wet weight, macroscopic and microscopic parameters, and COX-2 expression. In other groups etoricoxib (selective COX-2 inhibitor), indomethacin (non-selective COX inhibitor), thalidomide (selective TNF-alpha inhibitor), pentoxifyllin (non-selective TNF-alpha inhibitor) were added 1 h before IFS administration. The classical protocol using three doses of Mesna was also evaluated and compared with two extra doses of etoricoxib or indomethacin. RESULTS: COX-2 was expressed significantly 24 h after IFS administration mainly in myofibroblasts and mast cells evaluated by immunohistochemistry. Treatment 1 h before IFS injection with etoricoxib, indomethacin, thalidomide, and pentoxifylline reduced COX-2 expression and some macroscopic and microscopic parameters in IFS-induced HC. Moreover, addition of etoricoxib or indomethacin with the last two doses of Mesna was more efficient than three doses of Mesna alone when evaluated microscopically. CONCLUSIONS: COX-2 participates in the pathogenesis of IFS-induced HC and the treatment with COX and TNF-alpha inhibitors reduced COX-2 expression. The addition of COX-inhibitors to the last two doses of Mesna represents a new therapeutic strategy of preventing HC.