Influence of mesna on urotoxic effects of selected bromosubstituted analogs of ifosfamide.
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.
Kuśnierczyk
H
H
Department of Tumor Immunology, Institute of Immunology and Experimental Therapy, Wrocław, Poland.
Konarski
L
L
Kowalski
P
P
Radzikowski
C
C
D000284:Administration, Oral; D000818:Animals; D003556:Cystitis / Q000139:chemically induced / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D007069:Ifosfamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008452:Maximum Allowable Concentration; D015080:Mesna / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009336:Necrosis; D013237:Stereoisomerism; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology
C097983:chlorobromofosfamide; D015080:Mesna; D007069:Ifosfamide