Abstract
Chemotherapy with oxazaphosphorines, such as cyclophosphamide (CYP), is often limited by unacceptable urotoxicity. Without uroprotection, hemorrhagic cystitis (HC) becomes dose-limiting. To compare the uroprotective efficacy of classical 2-mercaptoethanesulfonic acid (Mesna) treatment with dexamethasone in CYP-induced HC, male Wistar rats (150-200 g; N = 6 in each group) were treated with saline or Mesna (40 mg/kg, ip) immediately and 4 and 8 h after ip administration of CYP (200 mg/kg). One, 2 or 3 doses of Mesna were replaced with dexamethasone (1 mg/kg, ip). The animals were sacrificed 24 h later. Cystitis was evaluated by determining the changes in bladder wet weight (BWW) and by macroscopic and microscopic analysis. CYP treatment induced a marked increased in BWW (162%, P<0.05), which was significantly inhibited by treatment with 3 doses of Mesna (P<0.05; 80%). The replacement of 1 or 2 doses of Mesna with dexamethasone reduced the increase in BWW by 83.3 and 95%, respectively. Macroscopic analysis of the bladder of rats with CYP-induced HC showed severe edema and hemorrhage, confirmed by microscopic analysis, that also showed mucosal erosion, inflammatory cell infiltration and ulcerations. The replacement of 1 or 2 doses of Mesna with dexamethasone inhibited the CYP-induced increase in BWW and almost abolished the macroscopic and microscopic alterations, with no significant difference between the effects of Mesna and dexamethasone, indicating that both drugs were efficient in blocking HC. However, although the replacement of all Mesna doses with dexamethasone reduced the edema, it did not prevent HC, suggesting that Mesna is necessary for the initial uroprotection.
Highlights
Cyclophosphamide (CYP), a cytotoxic alkylating agent, is used in chemotherapeutic regimens of lymphoproliferative disorders, certain solid tumors, and non-neoplastic diseases such as nephrotic syndrome, systemic lupus erythematosus and rheumatoid arthritis [1]
mercaptoethanesulfonic acid (Mesna) is indicated to prevent the occurrence of hemorrhagic cystitis, but is not effective when the lesion has been established
We demonstrated that cytokines like TNF-a and IL-1 were crucial mediators involved in these inflammatory events and in urothelial damage and hemorrhage [11]
Summary
Cyclophosphamide (CYP), a cytotoxic alkylating agent, is used in chemotherapeutic regimens of lymphoproliferative disorders, certain solid tumors, and non-neoplastic diseases such as nephrotic syndrome, systemic lupus erythematosus and rheumatoid arthritis [1]. We demonstrated that cytokines like TNF-a and IL-1 were crucial mediators involved in these inflammatory events and in urothelial damage and hemorrhage [11]. The aim of the present study was to investigate the effects of dexamethasone in CYP-induced hemorrhagic cystitis and propose an alternative posologic regimen of lower cost compared to the use of Mesna in the prevention of this type of cystitis.
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Schedule a callMore From: Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
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