title: Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate.
abstract: OBJECTIVE
  Primitive quiescent chronic myeloid leukemia (CML) cells are biologically resistant to imatinib mesylate, an inhibitor of the p210(BCR-ABL) kinase. The present study was designed to investigate whether either continuous or intermittent exposure of these cells to granulocyte-colony stimulating factor (G-CSF) in vitro can overcome this limitation to the effectiveness of imatinib mesylate therapy.
  
  
  METHODS
  CD34(+) leukemic cells were isolated from six newly diagnosed chronic phase CML patients and cultured for 12 days in serum-free medium with or without G-CSF and/or imatinib mesylate present either continuously or intermittently (three cycles of G-CSF for 0, 1, or 4 days +/- imatinib mesylate for 0, 3, or 4 days). Every 4 days, the number of residual undivided viable cells and the total number of viable cells present were measured.
  
  
  RESULTS
  Intermittent but not continuous exposure to G-CSF significantly accelerated the disappearance in vitro of initially quiescent CD34(+) CML cells. This resulted in 3- and 5-fold fewer of these cells remaining after 8 and 12 days, respectively, relative to continuous imatinib mesylate alone (P < 0.04). Cultures containing imatinib mesylate and intermittently added G-CSF also showed the greatest reduction in the total number of cells present after 12 days (5-fold more than imatinib mesylate alone).
  
  
  CONCLUSIONS
  Intermittent exposure to G-CSF can enhance the effect of imatinib mesylate on CML cells by specifically targeting the primitive quiescent leukemic elements. A protocol for treating chronic-phase CML patients with imatinib mesylate that incorporates intermittent G-CSF exposure may offer a novel strategy for obtaining improved responses in vivo.
authors.affiliation: Section of Experimental Haematology, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Queen Elizabeth Building, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, Scotland, UK.
authors.forename: Heather G
authors.initials: HG
authors.lastname: Jørgensen
authors.forename: Mhairi
authors.initials: M
authors.lastname: Copland
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Allan
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.forename: Allen
authors.initials: A
authors.lastname: Eaves
authors.forename: Connie
authors.initials: C
authors.lastname: Eaves
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001752:Blast Crisis; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004338:Drug Combinations; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016895:Culture Media, Serum-Free; D004338:Drug Combinations; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl