Cyclooxygenase-2 expression on ifosfamide-induced hemorrhagic cystitis in rats.
OBJECTIVE
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.
Macedo
Francisco Yuri Bulcao
FY
Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Rua Coronel Nunes de Melo, 1315, Rofolfo Teofilo, 60430-270, Fortaleza, CE, Brazil. yuribulcao@gmail.com
Baltazar
Fátima
F
Almeida
Paulo Roberto Carvalho
PR
Távora
Fábio
F
Ferreira
Francisco Valdeci
FV
Schmitt
Fernando C
FC
Brito
Gerly Anne Castro
GA
Ribeiro
Ronaldo Albuquerque
RA
D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D003556:Cystitis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D004359:Drug Therapy, Combination; D000077613:Etoricoxib; D006470:Hemorrhage / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D007069:Ifosfamide / Q000009:adverse effects*; D007124:Immunoenzyme Techniques; D007213:Indomethacin / Q000627:therapeutic use; D008297:Male; D015080:Mesna / Q000627:therapeutic use; D010431:Pentoxifylline / Q000627:therapeutic use; D020011:Protective Agents / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000627:therapeutic use; D013792:Thalidomide / Q000627:therapeutic use
D052246:Cyclooxygenase 2 Inhibitors; D020011:Protective Agents; D011725:Pyridines; D013450:Sulfones; D013792:Thalidomide; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015080:Mesna; D010431:Pentoxifylline; D007069:Ifosfamide; D000077613:Etoricoxib; D007213:Indomethacin