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Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia
Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Ph-positive leukemias. At a once-daily dose and a relatively short half-life of 3-5 hours, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or l...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038787/ https://www.ncbi.nlm.nih.gov/pubmed/20111071 http://dx.doi.org/10.1038/leu.2009.302 |
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author | Fei, Fei Stoddart, Sonia Müschen, Markus Kim, Yong-mi Groffen, John Heisterkamp, Nora |
author_facet | Fei, Fei Stoddart, Sonia Müschen, Markus Kim, Yong-mi Groffen, John Heisterkamp, Nora |
author_sort | Fei, Fei |
collection | PubMed |
description | Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Ph-positive leukemias. At a once-daily dose and a relatively short half-life of 3-5 hours, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low dose dasatinib monotherapy will be effective in causing irreversible apoptosis in Ph-positive ALL, but suggest that combined treatment with dasatinib and drugs such as AMD3100 may be effective. |
format | Text |
id | pubmed-3038787 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
record_format | MEDLINE/PubMed |
spelling | pubmed-30387872011-02-14 Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia Fei, Fei Stoddart, Sonia Müschen, Markus Kim, Yong-mi Groffen, John Heisterkamp, Nora Leukemia Article Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Ph-positive leukemias. At a once-daily dose and a relatively short half-life of 3-5 hours, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low dose dasatinib monotherapy will be effective in causing irreversible apoptosis in Ph-positive ALL, but suggest that combined treatment with dasatinib and drugs such as AMD3100 may be effective. 2010-01-28 2010-04 /pmc/articles/PMC3038787/ /pubmed/20111071 http://dx.doi.org/10.1038/leu.2009.302 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Fei, Fei Stoddart, Sonia Müschen, Markus Kim, Yong-mi Groffen, John Heisterkamp, Nora Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia |
title | Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia |
title_full | Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia |
title_fullStr | Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia |
title_full_unstemmed | Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia |
title_short | Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia |
title_sort | development of resistance to dasatinib in bcr/abl-positive acute lymphoblastic leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038787/ https://www.ncbi.nlm.nih.gov/pubmed/20111071 http://dx.doi.org/10.1038/leu.2009.302 |
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