Toxicity of ASTA Z 7557 (INN mafosfamide) to normal- and leukemic stem cells: Implications for autologous bone marrow transplantation

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Abstract
The activity of the in vitro active cyclophosphamide metabolite ASTA Z 7557 against pluripotent hemo-poietic stem cells (CFU-S), in vitro myeloid precursor cells (CFU-C) and clonogenic leukemic cells (LCFU-S) was evaluated in a rat model for human acute myelocytic leukemia (BNML). LCFU-S were most sensitive (D0 = 10.9 × 10-6 M), followed by CFU-C (D0 = 16.4 × 10-6 M), while CFU-S were least sensitive (D0 = 22.1 × 10-6 M). Per cell population there were considerable variations in response when identical drug concentrations were tested in different experiments under the same standardized conditions. Furthermore, the concentration of leukemic cells in a normal marrow cell suspension appeared to correlate with the cytotoxic action of the drug against leukemia. A decreased cytotoxicity was already observed in mixtures containing 1 leukemic cell per 10 normal marrow cells. The implications of these findings in the BNML model for human autologous bone marrow transplantation are discussed.