DNA-dependent protein kinase activity correlates with clinical and in vitro sensitivity of chronic lymphocytic leukemia lymphocytes to nitrogen mustards

被引:82
作者
Muller, C
Christodoulopoulos, G
Salles, B
Panasci, L
机构
[1] Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
[2] CNRS UPR 9062, Inst Pharmacol & Biol Struct, Toulouse, France
关键词
D O I
10.1182/blood.V92.7.2213.2213_2213_2219
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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, (C) 1998 by The American Society of Hematology.
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页码:2213 / 2219
页数:7
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