期刊
BLOOD
卷 99, 期 2, 页码 664-671出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.V99.2.664
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资金
- NCI NIH HHS [R01 CA069008, R01 CA085972, R01 CA85972, R01 CA69008, T32 CA09441] Funding Source: Medline
The adenosine triphosphate binding-site-directed agent STI571 and the tyrphostin adaphostin are undergoing evaluation as bcr/abl kinase inhibitors. The current study compared the effects of these agents on the survival of K562 cells, bcr/abl-transduced FDC-P1 cells, and myeloid progenitors from patients with chronic myelogenous leukemia (CML) compared with healthy donors. Treatment of K562 cells with 10 muM adaphostin resulted in decreased p210(bcr/abl) polypeptide levels in the first 6 hours, followed by caspase activation and accumulation of apoptotic cells in less than 12 hours. By 24 hours, 90% of the cells were apoptotic and unable to form colonies. In contrast, 20 muM STI571 caused rapid inhibition of bcr/abl autophosphorylation without p210(bcr/abl) degradation. Although this was followed by the inhibition of Stat5 phosphorylation and the down-regulation of BCI-x(L) and Mcl-1, only 7%+/-3% and 25%+/-9% of cells were apoptotic at 16 and 24 hours, respectively. Instead, the cytotoxic effects of STI571 became more pronounced with prolonged exposure, with IC90 values greater than 20 muM and 1.0+/-0.6 muM after 24 and 48 hours, respectively. Consistent with these results, 24-hour adaphostin exposure inhibited CML granulocyte colony-forming units (CFU-G) (median IC50,12 muM) but not normal CFU-G (median IC50, greater than 20 muM), whereas 24-hour STI571 treatment had no effect on CML or normal CFU-G. Additional experiments revealed that STI571-resistant K562 cells remained sensitive to adaphostin. Moreover, the combination of STI571 + adaphostin Induced more cytotoxicity In K562 cells and In CML CFU-G than either agent alone did. Collectively, these results Identify adaphostin as a mechanistically distinct CML-selective agent that retains activity In STI571-resistant cell lines. (Blood. 2002;99:664-671) (C) 2002 by The American Society of Hematology.
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