Detection of centrosome aberrations in disease-unrelated cells from patients with tumor treated with tyrosine kinase inhibitors.
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.
Giehl
Michelle
M
III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.
Leitner
Armin
A
Haferlach
Claudia
C
Duesberg
Peter
P
Hofmann
Wolf-Karsten
WK
Hofheinz
Ralf
R
Seifarth
Wolfgang
W
Hochhaus
Andreas
A
Fabarius
Alice
A
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
D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; C471992:bosutinib; D000069439:Dasatinib