title: Hematopoietic growth factor stimulation and cytarabine cytotoxicity in vitro: effects in untreated and relapsed or primary refractory acute myeloid leukemia cells.
abstract: Stimulation of clonogenic acute myeloid leukemia (AML) cells by hematopoietic growth factors (HGF) is capable of enhancing cytosine-arabinoside (Ara-C) cytotoxicity in vitro. Until now it has not been known to what extent in vitro Ara-C cytotoxicity can be restored by HGF stimulation in samples from previously treated AML patients. Therefore, we studied the individual effects of the hematopoietic growth factors (HGF) granulocyte colony-stimulating factor (G-CSF), interleukin-3 (IL-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation on the Ara-C sensitivity of clonogenic leukemic cells from six patients with newly diagnosed AML. These results were directly compared with the outcome using AML samples from the same patients at relapse or primary refractory AML. In one patient, a sample of the second relapse was also studied. The results were expressed as IC50 values, and were used to calculate sensitivity ratios, defined as the ratio of the IC50 value with drug exposure alone and with HGF plus Ara-C. In AML samples treated with Ara-C alone and no HGF, IC50 values of Ara-C in relapsed/refractory AML were greater than IC50 values of AML cells at diagnosis. Addition of either HGF enhanced the Ara-C cytotoxicity for the relapsed samples significantly (for G-CSF p = 0.036, IL-3 p = 0.036, and for GM-CSF p = 0.036). The values of Ara-C sensitization of AML samples due to HGF at relapse did not significantly differ from those at diagnosis. However, enhancement of Ara-C cytotoxicity to AML progenitors by IL-3 or GM-CSF stimulation was significantly less in the cell specimens from AML recurrence patients as compared with the original diagnosis samples. In three AML samples at diagnosis and at their relapse, Ara-C incorporation into the DNA was determined. IL-3 stimulation enhanced Ara-C incorporation in all samples tested. Nevertheless, Ara-C incorporation in the relapsed samples was significantly less than that in the diagnosis samples of the same patients. A good correlation between Ara-C incorporation and bromodeoxyuridine (BrdU) incorporation was found. The results indicate that HGF stimulation in relapsed/refractory AML enhances Ara-C cytotoxicity, but not to the level that was observed with AML samples at diagnosis.
authors.affiliation: Department of Hematology, Erasmus University, Rotterdam, The Netherlands.
authors.forename: P A
authors.initials: PA
authors.lastname: te Boekhorst
authors.forename: B
authors.initials: B
authors.lastname: Löwenberg
authors.forename: P
authors.initials: P
authors.lastname: Sonneveld
mesh_terms: D000328:Adult; D000368:Aged; D001973:Bromodeoxyuridine / Q000378:metabolism; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014410:Tumor Stem Cell Assay
chemical_list: D004273:DNA, Neoplasm; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D001973:Bromodeoxyuridine