THE EFFECT OF A COMBINED PURGING WITH MAFOSFAMIDE AND HYPERTHERMIA ON MURINE HEMATOPOIETIC STEM-CELLS AND LEUKEMOGENIC CELLS

The in vitro purging effect of mafosfamide combined with hyperthermia was studied in a murine model. The survival of normal clonogenic progenitors (d-9 CFU-S and CFU-GM) and WEHI 3-B leukaemic clonogenic cells (CFU-L) were compared. At 37-degrees-C, CFU-L proved to be significantly more sensitive to mafosfamide than either of the normal progenitors. When mafosfamide was combined with 42.5-degrees-C hyperthermia for 1 h, an additive effect was observed: at a dose of 5 mug/ml mafosfamide, the survival of CFU-L was nearly two logs lower than that observed at 37-degrees-C, while 37.7% of CFU-S survived the purging. The repopulating capacity of surviving bone marrow CFU-S was not altered: a similar 60 d survival of supralethally irradiated recipients transplanted with comparable graft sizes from purged or non-purged bone marrow was observed. When bone marrow suspensions containing WEHI 3-B cells were purged with 5 mug/ml mafosfamide at 42.5-degrees-C and the minimal amount of bone marrow cells needed to protect supralethally irradiated mice were injected, leukaemia incidence was reduced to less than 10% as opposed to 100% of those injected with untreated bone marrow. Our results suggest that ex vivo hyperthermia may enhance the purging efficiency of mafosfamide.