Imatinib sensitizes CLL lymphocytes to chlorambucil.
The effect of imatinib on chlorambucil (CLB) cytotoxicity in chronic lymphocytic leukemia (CLL) lymphocytes was examined in vitro. Imatinib sensitizes the WSU and I83 human CLL cell lines, 10- and two-fold, respectively, to CLB. Furthermore, in primary cultures of malignant B-lymphocytes obtained from 12 patients with CLL (seven patients were untreated and five treated with CLB), imatinib synergistically sensitized these lymphocytes from two- to 20-fold to CLB. This synergistic effect was observed at concentrations of imatinib (</=10 microM), which are achievable in patients with minimal toxicity. Moreover, the combination of both drugs results in increased apoptosis in CLL cell lines. These results suggest that imatinib should be useful in improving the therapeutic index of CLB in CLL. The mechanism of action appears to involve imatinib inhibition of c-abl kinase activity with an associated decrease in CLB-induced Rad51 phosphorylation and CLB-induced Rad51 nuclear foci, suggesting that imatinib decreases Rad51-related DNA repair of CLB-induced DNA lesions. Altogether, our results suggest that imatinib is a promising adjuvant therapy to CLB treatment of CLL.
Aloyz
R
R
Lady Davis Institute for Medical Research, Sir Mortimer B Davis - Jewish General Hospital, Montreal, Quebec, Canada.
Grzywacz
K
K
Xu
Z-Y
ZY
Loignon
M
M
Alaoui-Jamali
M A
MA
Panasci
L
L
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D002699:Chlorambucil / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051135:Rad51 Recombinase; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D001549:Benzamides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D002699:Chlorambucil; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; C495153:RAD51 protein, human; D051135:Rad51 Recombinase