TKIs MAY INFLUENCE CENTROSOMES

Eur J Haematol. 2010 Apr 16. [Epub ahead of print]
Detection of centrosome aberrations in disease unrelated cells from tumor patients treated with tyrosine kinase inhibitors.
Giehl M, Leitner A, Haferlach C, Duesberg P, Hofmann WK, Hofheinz R, Seifarth W, Hochhaus A, Fabarius A.

III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.
Abstract

Abstract Objectives: 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 CML patients 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 CML patients treated with dasatinib and OM cells of three CML patients treated with bosutinib showed centrosomal alterations (mean, 14%) compared with 16 (10 OM and 6 fibroblasts) controls (mean, 3%). OM cells of five CML patients 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.