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


OBJECTIVE
To investigate the use of two antioxidants-amifostine and glutathione-for the prevention of experimental IFS- and ACR-induced HC.


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.
Batista
C K L P
CK
Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Rua Coronel Nunes de Melo, 1127, Rodolfo Teófilo, 60430-270, Fortaleza, CE, Brazil.
Mota
J M S C
JM
Souza
M L P
ML
Leitão
B T A
BT
Souza
M H L P
MH
Brito
G A C
GA
Cunha
F Q
FQ
Ribeiro
R A
RA
D000171:Acrolein / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D003556:Cystitis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D005978:Glutathione / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D007069:Ifosfamide / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D001743:Urinary Bladder / Q000473:pathology
D000931:Antidotes; D018906:Antineoplastic Agents, Alkylating; D011837:Radiation-Protective Agents; D000171:Acrolein; D005978:Glutathione; D004999:Amifostine; D007069:Ifosfamide