Comparative in vitro cytotoxicity of cyclophosphamide, its major active metabolites and the new oxazaphosphorine ASTA Z 7557 (INN mafosfamide).
Cyclophosphamide (CPA), the most commonly used alkylating agent in the treatment of a wide variety of hematologic and solid tumors, requires oxidation by hepatic microsomal enzymes to its active alkylating species. A number of alternative methods exist to simulate the in vitro cytotoxicity of CPA against animal and human tumors, including the co-incubation of CPA with the S-9 fraction of rat liver homogenates (S-9) and the use of either 4-hydroperoxy CPA (a stabilized form of a major blood-borne metabolite of CPA), phosphoramide mustard (PM, considered to be the ultimate intracellular alkylating metabolite of CPA), or ASTA Z 7557 [4-(2-sulfonatoethylthio)-CPA, a new oxazaphosphorine compound which after dissolution undergoes rapid spontaneous hydrolysis in vitro with liberation of 4-hydroxy-CPA]. Using a human tumor clonogenic assay (HTCA) we have quantitated the median molar inhibitory dose 50 (ID50) concentrations of S-9 activated-CPA, 4-hydroperoxy-CPA, PM, and ASTA Z 7557 against 107 previously untreated tumors, as well as determining the in vitro biological stability of the former three CPA metabolite preparations. 4-Hydroperoxy-CPA proved the most consistently cytotoxic (median molar ID50 = 5.7 X 10(-5)M) compound, followed by ASTA Z 7557, S-9 activated-CPA and PM in that order. Of additional interest S-9 activated CPA and PM proved relatively unstable biologically when frozen at -120 degrees C, whereas 4-hydroperoxy-CPA lost none of its cytotoxicity over a 36 day period during freezing.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002999:Clone Cells; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004355:Drug Stability; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats
C037933:Asta Z 7557; D003520:Cyclophosphamide