GM-CSF: modulation of biochemical and cytotoxic effects of tiazofurin in HL-60 cells.
Cytokines, such as granulocyte macrophage colony stimulating factor (GM-CSF) or interleukin-3 (IL-3) recruit quiescent cells into the cell cycle and sensitize these cells towards cell cycle specific chemotherapeutic agents. We examined the in vitro effects of GM-CSF on HL-60 cells and tested its modulatory influence on biochemical and cytotoxic effects seen with tiazofurin, a potent and specific inhibitor of IMP dehydrogenase. Incubation of HL-60 cells with 500 U/ml GM-CSF for 4 d enhanced cell proliferation, which was accompanied by a significant increase 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 incubated with 100 microM tiazofurin for 2 h, intracellular GTP decreased to 46% of untreated control cells. In HL-60 cells pretreated with GM-CSF, GTP pools decreased to 38% of control after incubation with tiazofurin which is 69% of the predicted value for additive effect. The MTT chemosensitivity assay yielded significantly decreased IC50 values for tiazofurin in HL-60 cells, preincubated with GM-CSF (IC50 decreased from 13 microM to 10 microM). Therefore our results suggest that combination therapy with GM-CSF and tiazofurin may be beneficial for the treatment of refractory leukaemia patients.
Fritzer
M
M
Institute of Medical Chemistry, University of Vienna Medical School, Austria.
Gharehbaghi
K
K
Pillwein
K
K
Chiba
P
P
Goldenberg
H
H
Szekeres
T
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000187:drug effects; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000473:pathology*; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012254:Ribavirin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; C033706:tiazofurin