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Comparative in vitro cytotoxicity of cyclophosphamide, its major active metabolites and the new oxazaphosphorine ASTA Z 7557 (INN mafosfamide).
- Source :
-
Investigational new drugs [Invest New Drugs] 1984; Vol. 2 (2), pp. 141-8. - Publication Year :
- 1984
-
Abstract
- 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)
- Subjects :
- Animals
Cell Line
Cell Survival drug effects
Cells, Cultured
Clone Cells
Colonic Neoplasms drug therapy
Colonic Neoplasms metabolism
Cyclophosphamide metabolism
Drug Stability
Humans
Microsomes, Liver metabolism
Rats
Colonic Neoplasms pathology
Cyclophosphamide analogs & derivatives
Cyclophosphamide pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0167-6997
- Volume :
- 2
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 6469507
- Full Text :
- https://doi.org/10.1007/BF00232343