title: Influence of mesna and cysteine on the systemic toxicity and therapeutic efficacy of activated cyclophosphamide.
abstract: Presumably the coadministration of the uroprotector mesna in cyclophosphamide treatment does not influence the systemic activity of its activated metabolite. This was newly investigated in a mouse model. The LD50 values of i.p. administered mafosfamide, a derivative of act. CP, were increased by the simultaneous i.p. administration of mesna (mafosfamide: mesna 1:2 on a molar weight basis) from 590 mg/kg to 750 mg/kg, and after i.v. injection of cytostatic and thiol from 505 mg/kg to 810 mg/kg. Administration of 2 X molar cysteine i.v. or i.p. to mafosfamide-treated animals was even more effective against its lethal toxicity (LD50 i.p. 1800 mg/kg and i.v. 1130 mg/kg). Bone marrow toxicity (severe leukocytopenia) was partially abolished by both thiols. Also the therapeutic efficacy of act. CP against L1210 leukemia in DBA2 mice was reduced by 50% in the presence of cysteine and of mesna. Compared with mesna the higher detoxification effect of cysteine is attributed to its longer half-life (t1/2 20 min vs 12 min of mesna) and presumably an accumulation of cysteine in some cell systems (distribution coefficient 1.20 ml/g vs 0.68 ml/g of mesna). Nevertheless, our study clearly demonstrates a distinct systemic deactivation of act. CP by mesna, which might be of clinical relevance.
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D003545:Cysteine / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D008623:Mercaptoethanol / Q000031:analogs & derivatives*; D015080:Mesna / Q000378:metabolism / Q000494:pharmacology*; D008657:Metabolic Clearance Rate; D051379:Mice; D010976:Platelet Count / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000494:pharmacology
chemical_list: D013438:Sulfhydryl Compounds; C048341:mafosfamide; D008623:Mercaptoethanol; D003520:Cyclophosphamide; D003545:Cysteine; D015080:Mesna