Effect of cyclophosphamide pretreatment on daunorubicin in rat acute leukaemia model

The total number of leukaemic cells at the time of therapy may affect the tissue and target cell distribution and antitumour efficacy of cytotoxic drugs. The effects of low dose cyclophosphamide pretreatment on daunorubicin concentrations in leukaemic bone marrow were investigated in rats. At day 12 after transplantation of the leukaemia, rats were injected intraperitoneally with cyclophosphamide (30 mg/kg). 2 days later the leukaemic rats received daunorubicin intravenously (7.5 mg/kg). Cyclophosphamide pretreatment led to a significant increase in daunorubicin concentration in the femoral bone marrow, by a factor of about 7. The log leukaemic stem cell kill (LCK) values, as estimated by a survival assay, were 1.8, 0.7, and 5.4 for the leukaemic rats injected with cyclophosphamide (day 12), with daunorubicin (day 14), or with cyclophosphamide (day 12) plus daunorubicin (day 14), respectively). The simultaneous administration of cyclophosphamide and daunorubicin at day 14, induced a LCK of 2.7, a value that was the sum of the LCKs of cyclophosphamide and daunorubicin alone. Low-dose cyclophosphamide pretreatment led to an increased daunorubicin accumulation in femoral bone marrow of leukaemic rats, and was synergistic with daunorubicin.