Inhibitory effect of imatinib on normal progenitor cells in vitro.
Imatinib is a novel tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. Side effects are mostly moderate; however, a dose-dependent hematologic toxicity affecting all hematopoietic lineages is observed clinically. The aim of this study was to investigate the effect of imatinib on normal hematopoietic stem and progenitor cells in vitro. A dose-dependent decrease in proliferation potential was found when CD34+ cells were expanded in serum-free medium supplemented with 6 growth factors and imatinib. Functionally, a decrease in colony-forming capacity was observed under increasing doses of imatinib. However, no such effect on more primitive cobblestone area-forming cells was detectable. Both withdrawal of stem cell factor from our expansion cultures or functional inhibition of c-kit led to a similar degree of inhibition of expansion, whereas the effect of imatinib was substantially greater at all dose levels tested. These data suggest a significant inhibitory effect of imatinib on normal CD34+ progenitor (but not stem) cells that is largely independent of c-kit signaling.
Bartolovic
Kerol
K
Department of Hematology and Oncology, University Medical Center II, Otfried-Müller-Str 10, 72076 Tübingen, Germany. tim.bruemmendorf@med.uni-tuebingen.de
Balabanov
Stefan
S
Hartmann
Ulrike
U
Komor
Martina
M
Boehmler
Andreas M
AM
Bühring
Hans-Jörg
HJ
Möhle
Robert
R
Hoelzer
Dieter
D
Kanz
Lothar
L
Hofmann
Wolf-Karsten
WK
Brümmendorf
Tim H
TH
D015703:Antigens, CD / Q000097:blood; D018952:Antigens, CD34 / Q000097:blood; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D007231:Infant, Newborn; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012016:Reference Values
D015703:Antigens, CD; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate