Biologic activity of two derivatives and six possible metabolites of cyclophosphamide (NSC-26271).
The biologic activity in terms of survival of normal hematopoietic stem, osteosarcoma, and L1210 leukemia cells was determined for the following compounds:cyclophosphamide, its derivatives isophosphamide and trophosphamide, its possible metabolites nor-nitrogen mustard, hydroxylamine mustard, 4-ketocyclophosphamide, and and acrolein, and two substitutes for its primary active metabolite 4-hydroxycyclosphamide anhydro-dimer (4-hydroxy-CP-anhydro-dimer) and 4-hydroperoxycyclophosphamide (4-hydroperoxy-CP). On a molar basis none of the compounds shows a better therapeutic ratio between osteosarcoma and bone marrow stem cells than the parent compound. The therapeutic ratio between L1210 leukemia and normal cells is slightly better for 4-hydroperoxy-CP only. It may be concluded that the conversion of 4-hydroxy-CP-anhydro-dimer and 4-hydroperoxy-CP to the primary active metabolite 4-hydroxycyclophosphamide differs quantitatively. Moreover, it appears that by the use of these precursors a better therapeutic ratio might be obtained for some malignancies but not for others.
D000171:Acrolein / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001711:Biotransformation; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006900:Hydroxylation; D007069:Ifosfamide / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009588:Nitrogen Mustard Compounds; D012516:Osteosarcoma / Q000188:drug therapy; D010078:Oxazines / Q000627:therapeutic use
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D010078:Oxazines; D000171:Acrolein; D003520:Cyclophosphamide; D007069:Ifosfamide