Effects of signal transduction inhibitor 571 in acute myelogenous leukemia cells.
STI571 is a 2-phenylalaminopyrimidine derivative that inhibits c-abl, Bcr-Abl, and platelet-derived growth factor receptor tyrosine kinases. Recently, inhibition of stem cell factor (SCF)-induced c-kit phosphorylation and cell proliferation by STI571 was reported in the human myeloid cell line MO7e. Because approximately 70% of acute myelogenous leukemia (AML) cases are c-kit positive, we evaluated in vitro effects of STI571 on c-kit-positive cell lines and primary AML blast cells. At concentrations >5 microM, the drug marginally inhibited SCF-independent proliferation of cell lines and most of AML blasts. Treatment of AML cells with cytarabine and STI571 showed synergistic effect at low concentrations. Western blotting analysis documented a distinct band of M(r) 145,000 specific for c-kit in cell lines and in AML samples. There was no correlation between the level of the c-kit expression evaluated by Western blotting and percentage of c-kit-positive blasts as measured by flow cytometry. Neither in cell lines nor in primary AML cells, c-kit autophosphorylation was detectable under standard growth conditions. SCF-induced phosphorylation of c-kit in MO7e cells was inhibited by STI571. In a c-kit-positive AML-4 cell line, as well as in AML samples, c-kit phosphorylation was not induced by SCF exposure, suggesting that in these cases, the receptor could not be functionally activated. In conclusion, with the exception of MO7e, SCF did not induce phosphorylation of c-kit, and cell proliferation was not modulated in the presence of STI571. We did not detect any SCF-independent c-kit phosphorylation in our experimental systems. Consequently, STI571 exerted only a limited inhibitory effect on the cell growth.
Scappini
B
B
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Onida
F
F
Kantarjian
H M
HM
Dong
L
L
Verstovsek
S
S
Keating
M J
MJ
Beran
M
M
D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000633:toxicity; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D007377:Interleukin-3 / Q000494:pharmacology; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000503:physiopathology*; D007958:Leukocyte Count; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects*; D019089:Stem Cell Factor / Q000494:pharmacology
D001549:Benzamides; D007377:Interleukin-3; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit