Abstract
Resistance to chlorambucil in chronic lymphocytic leukemia (CLL) has been associated with increased DNA repair. Specifically, inhibition of either c-abl, which modulates Rad51 directed homologous recombination or DNA-PK dependent nonhomologous end joining has been shown to sensitize primary CLL lymphocytes to chlorambucil. Here we report that inhibition of c-abl can result in a compensatory increase in DNA-PK and thus inhibition of both c-abl and DNA-PK optimally sensitizes CLL lymphocytes to chlorambucil. In this paper we report a drug-induced compensatory change between two DNA repair pathways with potential therapeutic implications in CLL therapy.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Alkylating / pharmacology*
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology*
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Benzamides
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Blotting, Western
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Chlorambucil / pharmacology*
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Comet Assay
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DNA-Activated Protein Kinase / antagonists & inhibitors*
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DNA-Activated Protein Kinase / metabolism
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Drug Resistance, Neoplasm
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Drug Synergism
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Humans
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Imatinib Mesylate
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
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Leukemia, Lymphocytic, Chronic, B-Cell / therapy
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Phosphorylation
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Piperazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-abl / metabolism
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Pyrimidines / pharmacology*
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Recombination, Genetic*
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents, Alkylating
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Benzamides
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Chlorambucil
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Imatinib Mesylate
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Proto-Oncogene Proteins c-abl
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DNA-Activated Protein Kinase
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nilotinib