title: The effect of G-CSF on the in vitro cytotoxicity of cytarabine and fludarabine in the FLAG combination in pediatric acute myeloid leukemia.
abstract: The combination of fludarabine, cytarabine (ara-C) and G-CSF (FLAG) is routinely used in the treatment of acute myeloid leukemia (AML). In this study we characterized the interactions between fludarabine, ara-C and G-CSF in vitro using AML blasts. Exposure to G-CSF alone resulted in a higher leukemic cell survival (LCS), which might be indicative of increased proliferation. The LCS decreased significantly from 69.7 to 54.0% when blasts were exposed to G-CSF 21 h prior to incubation with ara-C (p=0.01). In contrast, LCS increased significantly (from 55.6 to 69.0%; p=0.04) after sequential exposure to G-CSF and fludarabine. Exposure to 4 combinations of fludarabine (4 h; 0.14 microM and 0.55 microM) and ara-C (96 h; 0.21 and 0.82 microM) (FLA) resulted in additive cytotoxicity. The triple combination (FLAG), 21 h 5 microM G-CSF followed by 4 h fludarabine (0.14 and 0.55 microM) and finally ara-C (0.21 and 0.82 microM) for 96 h also resulted in an additive cell kill. In conclusion, these data support the clinical use of G-CSF in combination with ara-C, and the combination of ara-C and FLA. Pre-exposure to G-CSF before FLA (FLAG) did not result in increased cytotoxicity in our experiments, indicative of similar anti-leukemic activity.
authors.affiliation: Department of Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hubeek
authors.forename: Elena
authors.initials: E
authors.lastname: Litvinova
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Richard
authors.initials: R
authors.lastname: Broekhuizen
authors.forename: Eric G
authors.initials: EG
authors.lastname: Haarman
authors.forename: Dieuwke R
authors.initials: DR
authors.lastname: Huismans
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Gudrun
authors.initials: G
authors.lastname: Fleischhack
authors.forename: Ursula
authors.initials: U
authors.lastname: Creutzig
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
mesh_terms: D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D049109:Cell Proliferation; D002470:Cell Survival; D002648:Child; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008297:Male; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D014740:Vidarabine; C024352:fludarabine