title: Detection of centrosome aberrations in disease-unrelated cells from patients with tumor treated with tyrosine kinase inhibitors.
abstract: OBJECTIVE
  Tyrosine kinase inhibitors (TKIs) target various pathways associated with proliferation of aberrant clones in malignant diseases. Despite good response and acceptable tolerability, little is known concerning long-term toxicity. Furthermore, the influence of these inhibitors on disease-unrelated cells is not investigated yet.
  
  
  METHODS
  Centrosome aberrations are hallmarks of various cancers. We sought to evaluate the effect of TKIs on centrosomes of disease-unrelated cells. We examined cells of the oral mucosa (OM) and fibroblasts of patients with chronic myeloid leukemia (CML) treated with dasatinib and bosutinib. Results were compared with data from patients with CML treated with imatinib or nilotinib and with data from patients suffering from renal and hepatocellular carcinomas (RCC/HCC) treated with sorafenib or sunitinib. Cells of healthy donors served as controls.
  
  
  RESULTS
  OM cells (n = 12) and fibroblasts (n = 7) of patients with CML treated with dasatinib and OM cells of three patients with CML treated with bosutinib showed centrosomal alterations (mean, 14%) compared with 16 (10 OM and 6 fibroblasts) controls (mean, 3%). OM cells of five patients with CML and one patient with systemic mastocytosis treated with imatinib or nilotinib and of eight patients with RCC or HCC treated with sorafenib or sunitinib showed centrosome defects in a mean of 15%.
  
  
  CONCLUSIONS
  Our data have shown that TKI treatment of tumor patients may influence centrosomes in disease-unrelated cells or tissues. This may be important with regard to various observed side effects.
authors.affiliation: III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.
authors.forename: Michelle
authors.initials: M
authors.lastname: Giehl
authors.forename: Armin
authors.initials: A
authors.lastname: Leitner
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: Peter
authors.initials: P
authors.lastname: Duesberg
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Ralf
authors.initials: R
authors.lastname: Hofheinz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Seifarth
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Alice
authors.initials: A
authors.lastname: Fabarius
mesh_terms: D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity; D016022:Case-Control Studies; D018385:Centrosome / Q000187:drug effects* / Q000473:pathology; D000069439:Dasatinib; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use / Q000633:toxicity; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; C471992:bosutinib; D000069439:Dasatinib