Pharmacological and histopathological study of cyclophosphamide-induced hemorrhagic cystitis - comparison of the effects of dexamethasone and Mesna

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 CYPinduced 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.

A model of hemorrhagic cystitis induced with acrolein in mice

“…There is evidence that ACR reacts with mesna producing an inert thioether that is eliminated in the urine (19). Thus, in this model, as is also the case for humans or animals treated with oxazaphosphorine (20), mesna presented its uroprotective effect when administered systemically or locally.…”

“…Moreover, evidence also exists that ACR increases the release of IL-8 by neutrophils (26). In the present study, to validate the model of ACR-induced HC, the animals were treated with mesna, a classical uroprotector agent with established clinical (8) and experimental efficacy (20,27). The increase in BWW and Evans blue extravasation was blocked by pretreatment of the mice with mesna, regardless of local or systemic administration.…”

Cyclooxygenase-2 expression on ifosfamide-induced hemorrhagic cystitis in rats

“…The bladders were removed and emptied of their urinary contents. The best time to access HC in rats is between 24 and 48 h according to the literature (Morais et al 1999), as shown by the increase in bladder wet weight (BWW) of rats. BWW drops signiWcantly after 48 h. Hence, we chose 24 h as the right time to access IFS-induced HC.…”

Molecular Basis of Drug Interactions of Methotrexate, Cyclophosphamide and 5-Fluorouracil as Chemotherapeutic Agents in Cancer

“…CP is mainly used in the treatment of blood cancer, brain cancer, leukemia and some solid tumors (Pavan K. V., 2013 ). It is also used in the treatment of various nonneoplastic diseases like nephritic syndrome, systemic lupus erythematosus and rheumatoid arthritis (Morais et al, 1999). As CP is used to treat both neoplastic and non-neoplastic diseases, it is very important to assess the long-term carcinogenic potential of this drug (Travis et al, 1995).…”