Blood 2008,
PMID: 18056843
Konig, Heiko; Holyoake, Tessa L; Bhatia, Ravi
Imatinib mesylate (imatinib) is highly effective in the treatment of chronic myeloid leukemia (CML) but is less effective in eliminating CML stem cells. We investigated whether SKI-606, a potent Bcr-Abl and Src kinase inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors. CML and normal progenitors were cultured with SKI-606 or imatinib. SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34(+) cells and inhibited Src phosphorylation more potently than imatinib. However, SKI-606 and imatinib resulted in similar suppression of CML primitive and committed progenitor proliferation and growth in CFC and LTC-IC assays. Exposure to either agent alone or in combination resulted in only modest increase in apoptosis. Evaluation of downstream signaling pathways indicated that Akt and STAT5 activity was not changed, but a delayed increase in MAPK activity was seen at high concentrations of SKI-606. SKI-606 inhibited normal progenitor proliferation to a lesser extent than imatinib. SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors. However, SKI-606 does not demonstrate increased ability to eliminate primitive CML progenitors by apoptosis compared with imatinib, emphasizing the need for additional strategies besides Bcr-Abl kinase inhibition for curative therapy of CML.
Diseases/Pathways annotated by Medline MESH: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Document information provided by NCBI PubMed
Text Mining Data
Bcr-Abl ⊣ SKI-606: "
We investigated whether
SKI-606 , a potent
Bcr-Abl and Src kinase
inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors
"
Src ⊣ SKI-606: "
We investigated whether SKI-606 , a potent Bcr-Abl and Src kinase inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors
"
Bcr-Abl ⊣ SKI-606: "
We investigated whether SKI-606 , a potent Bcr-Abl and Src kinase inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors
"
Bcr-Abl ⊣ SKI-606: "
SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib
"
Bcr-Abl ⊣ Src: "
SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib
"
Src ⊣ SKI-606: "
SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib
"
Src ⊣ Bcr-Abl: "
SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib
"
Bcr-Abl ⊣ SKI-606: "
SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib
"
Bcr-Abl ⊣ SKI-606: "
SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors
"
Src ⊣ SKI-606: "
SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors
"
Bcr-Abl ⊣ SKI-606: "
SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors
"
Manually curated Databases
No curated data.