Bates Darcy J P, Lewis Lionel D, Eastman Alan, Danilov Alexey V
Department of Medicine.
Norris Cotton Cancer Center; Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA.
Br J Clin Pharmacol. 2015 Sep;80(3):493-501. doi: 10.1111/bcp.12624. Epub 2015 May 19.
The authors' aim was to conduct a proof-of-principle study to test whether c-Jun N-terminal kinase (JNK) phosphorylation and Noxa induction occur in peripheral blood chronic lymphocytic leukaemia (CLL) cells in patients receiving a vincristine infusion.
Patients with CLL received 2 mg vincristine by a 5-min intravenous infusion. Blood samples were collected at baseline and up to 6 h after the vincristine infusion, and assayed for JNK activation, Noxa induction and vincristine plasma concentrations.
Ex vivo treated peripheral CLL cells activated JNK in response to 10-100 nM vincristine in 6 h. Noxa protein expression, while variable, was also observed over this time frame. In CLL patients, vincristine infusion led to rapid (<1 h) JNK phosphorylation in peripheral blood CLL cells which was sustained for at least 4-6 h after the vincristine infusion. Noxa protein expression was not observed in response to vincristine infusion.
This study confirmed that vincristine can activate JNK but not induce Noxa in CLL cells in vivo. The results suggest that novel JNK-dependent drug combinations with vincristine warrant further investigation.
作者旨在进行一项原理验证研究，以测试接受长春新碱输注的慢性淋巴细胞白血病（CLL）患者外周血CLL细胞中是否发生c-Jun氨基末端激酶（JNK）磷酸化和Noxa诱导。
CLL患者通过5分钟静脉输注接受2mg长春新碱。在基线时以及长春新碱输注后长达6小时采集血样，检测JNK激活、Noxa诱导和长春新碱血浆浓度。
体外处理的外周CLL细胞在6小时内对10-100 nM长春新碱产生反应，激活JNK。在这个时间范围内也观察到Noxa蛋白表达，尽管存在差异。在CLL患者中，长春新碱输注导致外周血CLL细胞中JNK快速（<1小时）磷酸化，在长春新碱输注后至少持续4-6小时。未观察到长春新碱输注后Noxa蛋白表达。
本研究证实长春新碱可在体内激活CLL细胞中的JNK，但不诱导Noxa。结果表明，与长春新碱联合使用的新型JNK依赖性药物组合值得进一步研究。
