- 1 2008
- 2 Historic Papers
Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia
Leuk Lymphoma. 2008 Jan;49(1):19-26.
The Jackson Laboratory, Bar Harbor, ME 04609, USA. email@example.com Abstract The BCR-ABL kinase inhibitor imatinib has shown significant efficacy in chronic myeloid leukemia (CML) and is the standard front-line therapy for patients in chronic phase. However, a substantial number of patients are either primarily refractory or acquire resistance to imatinib. While a number of mechanisms are known to confer resistance to imatinib, increasing evidence has demonstrated a role for BCR-ABL-independent pathways. The Src-family kinases (SFKs) are one such pathway and have been implicated in imatinib resistance. Additionally, these kinases are key to the progression of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The dual SFK/BCR-ABL inhibitor dasatinib is now clinically available and has markedly greater potency compared with imatinib against native BCR-ABL and the majority of imatinib-resistant BCR-ABL mutants. Therefore, this agent, as well as other dual SFK/BCR-ABL inhibitors under development, could provide added therapeutic advantages by overcoming both BCR-ABL-dependent (i.e. BCR-ABL mutations) and -independent forms of imatinib resistance and delaying transition to advanced phase disease. In this review, we discuss the preclinical and clinical evidence demonstrating the involvement of SFKs in imatinib resistance and the progression of CML and Ph+ ALL, as well as the potential role of dual SFK/BCR-ABL inhibition in the management of these diseases.
PMID: 18203007 http://www.ncbi.nlm.nih.gov/pubmed/18203007
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate
PLoS One. 2008;3(10):e3593. Epub 2008 Oct 31.
Chou CJ, O'Hare T, Lefebvre S, Alvarez D, Tyner JW, Eide CA, Druker BJ, Gottesfeld JM.
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model.
PMID: 18974832 http://www.ncbi.nlm.nih.gov/pubmed/18974832
The Philadelphia chromosome: a brief review
Beard ME, Fitzgerald PH. Aust N Z J Med. 1988 Jun;18(4):617-23. Review. No abstract available.
THE DISTRIBUTION OF THE PHILADELPHIA CHROMOSOME IN PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA
WHANG J, FREI E 3rd, TJIO JH, CARBONE PP, BRECHER G. Blood. 1963 Dec;22:664-73. No abstract available. PMID: 14084628 [PubMed - indexed for MEDLINE]Free Article
Chronic granulocytic leukemia and the Philadelphia chromosome
FITZGERALD PH, ADAMS A, GUNZ FW. Blood. 1963 Feb;21:183-96. No abstract available. PMID: 13945361 [PubMed - indexed for MEDLINE]Free Article
The Philadelphia Chromosome and Leukemia
[No authors listed] Can Med Assoc J. 1961 May 20;84(20):1142. No abstract available. PMID: 20326755