GM-CSF - MODULATION OF BIOCHEMICAL AND CYTOTOXIC EFFECTS OF TIAZOFURIN IN HL-60 CELLS

Cytokines, such as granulocyte macrophage colony stimulating factor (G M-CSF) or interleukin-3 (IL-3) recruit quiescent cells into the cell c ycle and sensitize these cells towards cell cycle specific chemotherap eutic agents. We examined the in vitro effects of GM-CSF on HL-60 cell s and tested its modulatory influence on biochemical and cytotoxic eff ects seen with tiazofurin, a potent and specific inhibitor of IMP dehy drogenase. Incubation of HL-60 cells with 500 U/ml GM-CSF for 4 d enha nced cell proliferation, which was accompanied by a significant increa se in IMP dehydrogenase activity (from 2.22 in control cells to 3 . 70 nmol/mg/h in cells pretreated with GM-CSF). When HL-60 cells were inc ubated with 100 mum tiazofurin for 2 h, intracellular GTP decreased to 46% of untreated control cells. In HI,60 cells pretreated with GM-CSF , GTP pools decreased to 38% of control after incubation with tiazofur in which is 69% of the predicted value for additive effect. The MTT ch emosensitivity assay yielded significantly decreased IC50 values for t iazofurin in HL-60 cells, preincubated with GM-CSF (IC50 decreased fro m 13 muM to 10 muM). Therefore our results suggest that combination th erapy with GM-CSF and tiazofurin may be beneficial for the treatment o f refractory leukaemia patients.