[Ifosfamide-induced urinary bladder lesion and its inhibition by mesna]

This study examined the characteristics of urinary bladder lesions (cystitis) induced by ifosfamide (IF), an antitumor agent, and their inhibition by mesna in rats. Single i.v. doses of 50 mg/kg or more of IF induced cystitis characterized by increased bladder weight with mucosal hemorrhage and edema within 3 hr, with a plateau being reached 1 to 3 days after the injection. This change occurred earlier than myelotoxicity. Injection of IF to ureter-ligated rats did not induce the cystitis. Also, when IF was infused to one of a pair of rats in which the ureters had been crossed, the cystitis occurred only in the non-injected member of the pair whose bladder received urine flow from the IF-injected rat. Cystitis did not occur with direct injection of 10 mg of IF into the urinary bladder, but did with injection of the metabolite, 14 micrograms of acrolein. These findings show that IF-induced cystitis is not a systemic effect like myelotoxicity or an antitumor effect but a local effect. The cystitis could be completely inhibited by mesna, and this effect, which was dose-dependent, occurred from one-tenth of the IF dose. The effect was strongest when mesna was administrated within 1 hr of the IF injection. There was little difference in the effect between single and divided doses. The combined administration of IF with mesna did not lower the antitumor effect of IF.