Abstract
The objective of this study is to investigate the role of DNA-dependent protein kinase (DNA-PK) in the chronic lymphocytic leukemia (CLL) lymphocyte response to nitrogen mustard therapy. DNA-PK is a nuclear serine/threonine kinase that functions in DNA double-strand break repair and in the joining process in recombination mechanisms. In a series of 34 patients with B-CLL, either untreated (n = 16) or resistant to chlorambucil (n = 18), the kinase activity of the complex, as determined by its capacity to phosphorylate a peptide substrate in vitro, is increased in the resistant samples as compared with the untreated ones (24.4 +/- 2.6 arbitrary units [a.u.] [range, 12.7 to 55.8 a.u.] versus 8.1 +/- 2.8 a.u. [range, 0.9 to 44.5 a.u.], respectively (P < .0001]), independent of other clinical and biological factors. Linear regression analysis shows an excellent correlation between the level of DNA-PK activity and the inherent in vitro sensitivity of CLL lymphocytes to chlorambucil (r = .875, P =.0001). The regulation of DNA-PK activity was associated with increased DNA-binding activity of its regulatory subunit, the Ku heterodimer, in resistant samples. These results suggest that this activity is a determinant in the cellular response to chlorambucil and participates in the development of nitrogen mustard-resistant disease. The increase in DNA-PK activity might contribute to the enhanced cross-link repair that we previously postulated to be a primary mechanism of resistance to nitrogen mustards in CLL.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Amino Acid Sequence
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Antineoplastic Agents, Alkylating / pharmacology*
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Antineoplastic Agents, Alkylating / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Chlorambucil / pharmacology
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Chlorambucil / therapeutic use
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Cross-Linking Reagents / pharmacology*
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Cross-Linking Reagents / therapeutic use
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Cyclophosphamide / administration & dosage
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Cyclophosphamide / pharmacology
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Cyclophosphamide / therapeutic use
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DNA Damage
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DNA Repair / drug effects*
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DNA, Neoplasm / drug effects
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DNA, Neoplasm / metabolism*
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DNA-Activated Protein Kinase
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DNA-Binding Proteins*
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Doxorubicin / administration & dosage
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Drug Resistance, Neoplasm
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Female
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Male
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Middle Aged
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Molecular Sequence Data
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Neoplasm Proteins / metabolism*
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / enzymology
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Nitrogen Mustard Compounds / pharmacology*
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Nitrogen Mustard Compounds / therapeutic use
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Nuclear Proteins
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Peptides / metabolism
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Phosphorylation
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Prednisone / administration & dosage
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / metabolism*
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Recombination, Genetic / drug effects*
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Treatment Outcome
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Tumor Cells, Cultured / drug effects
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Vincristine / administration & dosage
Substances
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Antineoplastic Agents, Alkylating
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Cross-Linking Reagents
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DNA, Neoplasm
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DNA-Binding Proteins
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Neoplasm Proteins
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Nitrogen Mustard Compounds
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Nuclear Proteins
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Peptides
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Chlorambucil
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Vincristine
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Doxorubicin
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Cyclophosphamide
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DNA-Activated Protein Kinase
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PRKDC protein, human
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Protein Serine-Threonine Kinases
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Prednisone
Supplementary concepts
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CHOP protocol
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COP protocol 2