title: Imatinib and nilotinib inhibit hematopoietic progenitor cell growth, but do not prevent adhesion, migration and engraftment of human cord blood CD34+ cells.
abstract: BACKGROUND
  The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more potent than imatinib towards BCR-ABL in vitro. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation, differentiation, adhesion, migration and engraftment capacities of human cord blood CD34(+) cells.
  
  
  METHODS
  After a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD/SCID/IL-2Rγ (null) mice.
  
  
  RESULTS
  TKIs did not affect LTC-IC frequencies despite in vitro inhibition of CFC formation due to inhibition of CD34(+) cell cycle entry. Adhesion of CD34(+) cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations. Migration through a SDF-1α gradient was not changed by cell culture in the presence of TKIs. Finally, bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model. No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for KIT.
  
  
  CONCLUSIONS
  These data suggest that combining non-myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe.
authors.affiliation: Hematology Research Unit, Giga-I3, University of Liège, Liège, Belgium. lbelle@ulg.ac.be
authors.forename: Ludovic
authors.initials: L
authors.lastname: Belle
authors.forename: France
authors.initials: F
authors.lastname: Bruck
authors.forename: Jacques
authors.initials: J
authors.lastname: Foguenne
authors.forename: André
authors.initials: A
authors.lastname: Gothot
authors.forename: Yves
authors.initials: Y
authors.lastname: Beguin
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baron
authors.forename: Alexandra
authors.initials: A
authors.lastname: Briquet
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D005312:Fetal Blood / Q000166:cytology* / Q000637:transplantation*; D005353:Fibronectins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D039041:Integrin alpha4beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D001549:Benzamides; C527276:CXCR4 protein, human; D005353:Fibronectins; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; C545354:retronectin; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C498826:nilotinib