title: DNA-Dependent protein kinase activity correlates with clinical and in vitro sensitivity of chronic lymphocytic leukemia lymphocytes to nitrogen mustards.
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.
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (CNRS UPR 9062), Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Muller
authors.forename: G
authors.initials: G
authors.lastname: Christodoulopoulos
authors.forename: B
authors.initials: B
authors.lastname: Salles
authors.forename: L
authors.initials: L
authors.lastname: Panasci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002699:Chlorambucil / Q000494:pharmacology / Q000627:therapeutic use; D003432:Cross-Linking Reagents / Q000494:pharmacology* / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D009687:Nuclear Proteins; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D011241:Prednisone / Q000008:administration & dosage; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011995:Recombination, Genetic / Q000187:drug effects*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009588:Nitrogen Mustard Compounds; D009687:Nuclear Proteins; D010455:Peptides; D002699:Chlorambucil; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D011241:Prednisone