Bromofosfamides, the group of novel compounds closely related to
ifosfamide, are currently in the stage of advanced preclinical evaluation.
Ifosfamide, although itself the effective
antineoplastic drug useful in situations which have proved refractory to
cyclophosphamide therapy, has the side-effect toxicities caused by its metabolities that pose clinically a very real problem. One of their manifestations is the severe urinary tract toxicity which now could be adequately managed by conjunctive administration of
mesna (
sodium 2-mercaptoethane sulphonate). In this study we have compared the magnitude of urotoxic effects elicited by
ifosfamide and two
bromofosfamide compounds--racemate and S(-) isomer of
chlorobromofosfamide (ClBrs)--selected previously on the base of their superior antitumor activity in advanced animal
tumor models. The urotoxic effects, expressed by the increase of urinary bladder weight and histopathologically defined organ wall
edema, were estimated in healthy mice 24 h following single intraperitoneal or
oral administrations of tested compounds which were applied in amounts equal to curative, sublethal or lethal doses. It was found that the expression of toxic effects revealed by both ClBrs was statistically significantly lower as compared to
ifosfamide.
Mesna coadministration prevented urotoxic effects almost completely in mice treated with
ifosfamide or racemic ClBr. Somewhat lower efficacy of uroprotection with
mesna was observed in the case of S(-) isomer of ClBr.