PHARMACOLOGICAL PURGING OF SYNGENEIC BONE-MARROW EXVIVO - EFFECT OF TREATMENT WITH DOXORUBICIN AND LONIDAMINE ON NORMAL AND LEUKEMIC-CELLS OF DBA/2 MICE

The in vivo effect of in vitro treatment with doxorubicin plus lonidamine on normal and leukaemic cells was investigated in a mouse model of syngeneic bone marrow transplantation. Different numbers of L5178Y tumour cells or normal bone marrow cells alone, or mixtures of bone marrow and leukaemic cells were incubated with doxorubicin (0.25, 0.5, 0.75, 1-mu-g/ml) and/or lonidamine (50-mu-g/ml) and reinfused in DBA/2 mice. Lonidamine potentiated the cytotoxic effect of doxorubicin dependent on doxorubicin dosage and tumour cell concentration. Survival after injection of 104 in vitro-treated tumour cells was 42% for doxorubicin 0.75-mu-g/ml alone versus 100% for the combination with lonidamine and 50% for doxorubicin 1-mu-g/ml alone versus 100% combination. Reinfusion of normal bone marrow incubated with doxorubicin alone or in combination with lonidamine in lethally irradiated mice did not occur in 12-14% of mice injected, indicating that the repopulating ability of stem cells was spared. These data suggest the potential usefulness of lonidamine in ex vivo purging of bone marrow before autologous bone marrow transplants in haemopoietic malignancies.