EFFECT OF CYTOKINES ON THE TOXICITY OF CYTOSTATIC DRUGS ON LEUKEMIC-CELLS IN-VITRO AND IN-VIVO

Most cytostatic drugs exert their effect on cells in active cell cycle . To improve the effect of cytostatic drugs we have tried, prior to tr eatment in vitro, to recruit tumor cells from G(0) with growth factors . Leukemic cells from the bone marrows of 26 patients with AML and CML in blast crisis were incubated with G-CSF, GM-CSF and IL-3 for 24 h p rior to incubation with cytostatic drugs. The cells were incubated wit h mitoxantrone, etoposide or daunorubicin for 1 h, or with Ara-C conti nuously. Prior to treatment, 4 patients with AML received GM-CSF for 2 4 h, after which blast cells from bone marrow were incubated with cyto static drugs. After incubation with the cytostatic drugs, cells were c ultured in a suspension culture for 4 d. The drug effect was determine d with a bioluminescence ATP method. Leukemic cells were significantly stimulated by all three cytokines compared to an untreated control. G M-CSF and IL-3 increased the amount of cells 3- to 4-fold and G-CSF in creased the amount 3 times compared to untreated cells. G-CSF signific antly enhanced the cytotoxic effect of daunorubicin, mitoxantrone, eto poside and Ara-C by 20-40%, while GM-CSF and IL-3 showed a significant ly increased toxicity for Ara-C only. Although the cytokines induced a higher percentage of cells killed with the cytostatic drugs, prolifer ation of the remaining cells resulted in an increased total number of cells fi om 1.5 to 3 times compared to the unstimulated incubations. W e conclude that cytokines induce a higher level of toxicity of cytosta tic drugs on leukemic cells, but the increased proliferation of the re maining cells may offset the clinical benefit.