Document Detail


Centrosome aberrations and G1 phase arrest after in vitro and in vivo treatment with the SRC/ABL inhibitor dasatinib.
MedLine Citation:
PMID:  18519516     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Dasatinib is a multitargeted inhibitor of ABL, the SRC family, and other tyrosine kinases. We sought to evaluate the effects of this drug on cell proliferation, centrosomes, mitotic spindles, and cell cycle progression in vitro and in vivo. DESIGN AND METHODS: Human dermal fibroblasts, Chinese hamster cells, human osteosarcoma cells, and blood and bone marrow mononuclear cells from 32 patients with chronic myeloid leukemia, gastrointestinal stromal tumor, and systemic mastocytosis as well as from six healthy individuals were investigated. The effects of dasatinib were compared with those of the ABL inhibitors imatinib and nilotinib, the SRC inhibitor PP2, and the ABL/LYN inhibitor INNO-406. RESULTS: Dasatinib induced G(1) phase arrest in all cell lines and this was associated with a decline in cyclin D1 levels. In vitro, centrosomal aberrations, a decrease of mitotic spindles, and G(1) phase arrest were observed. In patients, centrosome alterations were found in a median of 17% (range, 10-22%) of cells with a decrease of spindles in 8/18 patients. In comparison, imatinib, nilotinib and PP2 led to centrosome aberrations without G(1) phase arrest. INNO-406 was associated with centrosome aberrations and cell cycle arrest in G(1) phase. CONCLUSIONS: Dasatinib blocks the G(1)/S transition and inhibits cell growth. It induces centrosomal aberrations and a decrease of mitotic spindles. The effects suggest an involvement of SRC and ABL inhibition.
Authors:
Alice Fabarius; Michelle Giehl; Blanka Rebacz; Alwin Krämer; Oliver Frank; Claudia Haferlach; Peter Duesberg; Rüdiger Hehlmann; Wolfgang Seifarth; Andreas Hochhaus
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-06-02
Journal Detail:
Title:  Haematologica     Volume:  93     ISSN:  1592-8721     ISO Abbreviation:  Haematologica     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-01     Completed Date:  2008-10-09     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  1145-54     Citation Subset:  IM    
Affiliation:
III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Wiesbadener Strasse 7-11, 68305 Mannheim, Germany. alice.fabarius@med3.ma.uni-heidelberg.de
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*
Bone Marrow Cells / drug effects,  pathology
CHO Cells
Cell Division / drug effects
Cell Line, Tumor
Centrosome / drug effects*
Cricetinae
Cricetulus
Fibroblasts / physiology*
G1 Phase / drug effects,  genetics*
Genes, abl / drug effects*
Genes, src / drug effects*
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood,  drug therapy,  pathology
Osteosarcoma
Piperazines / pharmacology*,  therapeutic use
Pyrimidines / pharmacology*,  therapeutic use
Skin Physiological Phenomena
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Piperazines; 0/Pyrimidines; 152459-95-5/imatinib

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