title: Comparison of the effects of two kinase inhibitors, sorafenib and dasatinib, on chronic lymphocytic leukemia cells.
abstract: BACKGROUND
  With sorafenib displaying the highest affinities for Flt3, VEGFR (vascular endothelial growth factor receptor) and Raf and dasatinib for Abl and Src kinases, the profiles of kinases targeted by these inhibitors differ strongly.
  
  
  METHODS
  Dose-dependent effects of the inhibitors on freshly isolated chronic lymphocytic leukemia (CLL) cells were assessed as increased phosphatidylserine exposure. Inhibition by sorafenib and dasatinib of survival and anti-apoptotic signaling in CLL cells was examined by Western blot analysis.
  
  
  RESULTS
  Sorafenib uniformly induced apoptosis in CLL lymphocytes with a concentration inhibiting by 50% (IC50) of 8 mM, whereas the response to dasatinib was heterogeneous with the onset of inhibition at submicromolar concentrations but with IC50 values below 25 mM in only a few samples. At the respective pharmacologically achievable plasma concentrations, the inhibitors showed more efficient apoptosis induction by sorafenib than by dasatinib and less than additive mutual enhancement in combination. Co-culture with the bone marrow stroma cell line HS-5 increased the viability of untreated CLL cells but did not protect from sorafenib-induced apoptosis.
  
  
  CONCLUSIONS
  Sorafenib or dasatinib displayed sigmoidal or saturation-type dose-response relationships for apoptosis induction, which were uniform or highly divergent, respectively, among individual CLL samples and therefore might complement each other in their clinical potential for CLL.
authors: Department I of Internal Medicine, Center of Integrated Oncology Cologne Bonn, Germany.
authors: Mirjam
authors: M
authors: Kuckertz
authors: Michaela
authors: M
authors: Patz
authors: Aditya
authors: A
authors: Veldurthy
authors: Iris
authors: I
authors: Gehrke
authors: Julia
authors: J
authors: Claasen
authors: Lukas P
authors: LP
authors: Frenzel
authors: Clemens-Martin
authors: CM
authors: Wendtner
authors: Michael
authors: M
authors: Hallek
authors: Günter
authors: G
authors: Krause
mesh_terms: D001557:Benzenesulfonates / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects*; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007928:Lethal Dose 50; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology* / Q000503:physiopathology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D000077157:Sorafenib; D013844:Thiazoles / Q000008:administration & dosage*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles; D009536:Niacinamide; D000077157:Sorafenib; D000069439:Dasatinib