期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 149, 期 4, 页码 508-517出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1365-2141.2010.08106.x
关键词
leukaemia; B-lineage ALL; apoptosis; tyrosine kinase; SYK kinase inhibitors
类别
资金
- Parker Hughes Trust
- Hughes Chair in Molecular Oncology at Parker Hughes Institute
P>The present study found that the pentapeptide mimic C-61, targeting the substrate binding P-site of SYK tyrosine kinase acted as a potent inducer of apoptosis in chemotherapy-resistant SYK-expressing primary leukemic B-cell precursors taken directly from relapsed B-precursor leukaemia (BPL) patients (but not SYK-deficient infant pro-B leukaemia cells), exhibited favourable pharmacokinetics in mice and non-human primates, and eradicated in vivo clonogenic leukaemia cells in severe combined immunodeficient mouse xenograft models of chemotherapy-resistant human BPL at dose levels non-toxic to mice and non-human primates. These in vitro and in vivo findings provide proof of principle for effective treatment of chemotherapy-resistant BPL by targeting SYK-dependent anti-apoptotic blast cell survival machinery with a SYK P-Site inhibitor. Further development of C-61 may provide the foundation for therapeutic innovation against chemotherapy-resistant BPL.
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