COMBINATION OF HEMATOPOIETIC GROWTH-FACTORS CONTAINING IL-3 INDUCE ACUTE MYELOID-LEUKEMIA CELL SENSITIZATION TO CYCLE-SPECIFIC AND CYCLE NONSPECIFIC DRUGS

Laboratory studies have suggested that hematopoietic growth factors (G F), combined with cytosine-arabinoside (Ara-C) can enhance cytotoxic e ffects of this agent against acute myeloid leukemia (AML) cells. While clinical trials based on this growth factor/chemotherapy combination (GF/CT) are progressing with discordant results, further information r egarding the underlying mechanisms have been reported supporting this rationale and requiring additional investigation. To assess the role o f cytokinetic changes in the GF/CT strategy and to evaluate if chemoth erapeutic agents regimens other than Ara-C, when combined with GF, can enhance their cytotoxic effects, we have primed AML blasts with two c ytokine combinations and then exposed these cells to the S-phase speci fic agent Ara-C as well as to the phase non-specific drug daunorubicin (DNR) and to the alkylating agent 4-hydroperoxycyclophosphamide (4-HC ). The two cytokine combinations used for priming AML blasts were: (i) interleukin-3 (IL-3) + granulocyte-macrophage colony-stimulating fact or (GM-CSF) + granulocyte colony-stimutating factor (G-CSF); and (ii) GM + G-CSF. Cytokinetic analysis in ten AML samples and clonogenic gro wth of leukemic colonies (CFU-L) in methylcellulose were used to detec t proliferative and cytotoxic effects on AML samples. We report that i n AML clonogenic cell growth can be stimulated by cytokines in 50% of the samples (4/8), and that Ara-C sensitization clearly occurs in two out of these four samples. Among the different cytokine combinations t ested, the one containing IL3 was the most effective through a cytokin etic mechanism consistent with recruitment (averaged G(o) decrease p=0 .04; S-phase increase p=0.005). Furthermore we observed increased cyto toxicity also to the phase non-specific drugs DNR and 4-HC, which may be mediated by other mechanisms recently described. We conclude that G F/CT combinations may also be beneficial in regimens containing drugs other than Ara-C, used for AML treatment, including bone marrow transp lantation conditioning regimens.