Aloyz R, Grzywacz K, Xu Z-Y, Loignon M, Alaoui-Jamali M A, Panasci L
Lady Davis Institute for Medical Research, Sir Mortimer B Davis - Jewish General Hospital, Montreal, Quebec, Canada.
Leukemia. 2004 Mar;18(3):409-14. doi: 10.1038/sj.leu.2403247.
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.
在体外研究了伊马替尼对慢性淋巴细胞白血病（CLL）淋巴细胞中苯丁酸氮芥（CLB）细胞毒性的影响。伊马替尼分别使WSU和I83人CLL细胞系对CLB的敏感性提高了10倍和2倍。此外，在从12例CLL患者（7例未治疗，5例接受CLB治疗）获得的恶性B淋巴细胞原代培养物中，伊马替尼使这些淋巴细胞对CLB的敏感性协同提高了2至20倍。在伊马替尼浓度（≤10 microM）下观察到这种协同效应，该浓度在患者中可达到且毒性最小。此外，两种药物联合使用可导致CLL细胞系中凋亡增加。这些结果表明，伊马替尼应有助于提高CLB治疗CLL的治疗指数。作用机制似乎涉及伊马替尼对c-abl激酶活性的抑制，以及CLB诱导的Rad51磷酸化和CLB诱导的Rad51核灶的相关减少，这表明伊马替尼减少了CLB诱导的DNA损伤的Rad51相关DNA修复。总之，我们的结果表明，伊马替尼是CLB治疗CLL的一种有前景的辅助疗法。
