Toxicity of ASTA Z 7557 (INN mafosfamide) to normal- and leukemic stem cells: implications for autologous bone marrow transplantation.
The activity of the in vitro active cyclophosphamide metabolite ASTA Z 7557 against pluripotent hemopoietic 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 X 10(-6) M), followed by CFU-C (D0 = 16.4 X 10(-6) M), while CFU-S were least sensitive (D0 = 22.1 X 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.
D000818:Animals; D016026:Bone Marrow Transplantation; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D007942:Leukemia, Experimental / Q000628:therapy*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D051381:Rats; D011914:Rats, Inbred BN; D013234:Stem Cells / Q000187:drug effects*; D014182:Transplantation, Autologous; D014410:Tumor Stem Cell Assay
C037933:Asta Z 7557; D003520:Cyclophosphamide