Effects of cyclophosphamide and ifosfamide on neuroblastoma cells before and after activation by microsomes

Cyclophosphamide (CP) and Ifosfamide (IF) are of great importance in the therapy of neuroblastoma (NB). They are prodrugs which have to be activated by microsomes in order to become active compounds. We established a test system which allowed the activation of CP and IF by liver microsomes in the presence of NB cells. The data from these experiments showed that neuroblastoma cells (SK-N-SH, SK-N-LO and IMR-5) were unable to activate CP and IF, but in the presence of rat liver microsomes considerable cytotoxicity was achieved, similar to those of the preactivated derivatives maphosphamide (MP) and 4-hydroxy-ifosfamide (4-OH-IF). Compared to other compounds the final metabolite acrolein contributes significantly to the cytotoxicity of CP and IF, obviously through significant lowering of the glutathione levels in the cells. The incubation system as described allows the rapid determination of the cytotoxicity of CP and IF in the simultaneous presence of microsomes. The results show great differences in the sensibility of NB cells toCP and IF.