Two stable Fenton oxidation products of cyclophosphamide (NSC-26271) as precursors of 4-hydroxycyclophosphamide (NSC-196562) under physiologic conditions.
Cytostatic and chemical properties of two cyclophosphamide (CP) 4-peroxides, 4-hydroperoxycyclophosphamide and 4-hydroxycyclophosphamide anhydro-dimer, that were earlier isolated and identified after Fenton oxidation of CP, are summarized and discussed. Their cytostatic toxicities, which are quantitatively comparable to those of the primary metabolite of CP, 4-hydroxycyclophosphamide, are explained from their apparent spontaneous conversion to mono-oxidized forms of CP, both in vitro and in vivo. The conversion is shown to proceed via autocatalyzed reactions, which are thought to imply the occurrence of free radicals during deoxygenation. The point is raised whether any qualitative difference in cytotoxicity might be caused by the action of these free radicals. Current dose-effect studies of residual colony-forming ability after treatment of 3T6 mouse fibroblasts and Yoshida sarcoma cells in suspension culture are introduced. Further studies on the local toxic action of the radicals under in vivo conditions are necessary if the peroxides are to be introduced in local or regional clinical treatments.
D000171:Acrolein; D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000378:metabolism; D005609:Free Radicals; D007069:Ifosfamide / Q000031:analogs & derivatives; D007928:Lethal Dose 50; D008956:Models, Chemical; D010084:Oxidation-Reduction; D010545:Peroxides; D012517:Sarcoma, Yoshida / Q000188:drug therapy; D013997:Time Factors
D000970:Antineoplastic Agents; D005609:Free Radicals; D010545:Peroxides; D000171:Acrolein; D003520:Cyclophosphamide; D007069:Ifosfamide