Cell-cycle Disruptions and Apoptosis Induced by the Cyclophosphamide Derivative Mafosfamide

The effect of the cyclophosphamide derivative mafosfamide (ASTA Z 7557) was investigated in vitro in HL60 leukemic cells. Mafosfamide, which rapidly generates 4-hydroxycyclophosphamide after aqueous dissolution, was employed at doses ranging from 0.1 to 10 micrograms/mL. In unsynchronized cells, mafosfamide exposure was associated with an S-phase accumulation, a suggestion of a G2-phase arrest and morphological and biochemical evidence of apoptosis. In cells that had been synchronized by the double thymidine block method, S-phase progression was considerably delayed in the presence of mafosfamide. The apoptosis that was evident in mafosfamide-treated cells 12 hours after release from the thymidine block was found to occur in the presence of S-phase and G2-phase cell-cycle arrests. Taken together, the current data suggest that mafosfamide may have potential synergism with other anticancer agents that elicit similar cell-cycle arrests as well as with chemotherapeutic drugs that activate the apoptotic cascade.