Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents
Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents
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DOI：
10.1158/1078-0432.ccr-07-1061
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发表时间：
2008-01-01
影响因子：
11.5
通讯作者：
Niemeyer, Christina C.
中科院分区：
文献类型：
--
作者：
Leoni, Lorenzo M.;Bailey, Brandi;Niemeyer, Christina C.
目的：苯达莫司汀在常规烷化剂化疗难治性疾病患者中显示出临床活性。本研究的目的是表征苯达莫司汀的作用机制，并将其与结构相关的化合物进行比较。实验设计：苯达莫司汀在美国国家癌症研究所的体外抗肿瘤筛选中进行了分析。基于微阵列的基因表达谱，实时PCR，免疫印迹，细胞周期，和功能性DNA损伤修复分析被用来表征响应苯达莫司汀和比较它与苯丁酸氮芥和磷酰胺mustard.Results：苯达莫司汀显示一个独特的模式无关的其他DNA烷基化剂的活动。其作用机制包括激活DNA损伤应激反应和细胞凋亡，抑制有丝分裂检查点和诱导有丝分裂灾难。此外，与其他烷化剂，苯达莫司汀激活碱基切除DNA修复途径，而不是烷基转移酶DNA修复mechanism.Conclusion：这些结果表明，苯达莫司汀具有机械功能，区分它从其他烷化剂，并可能有助于其独特的临床疗效概况。
Purpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds.Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard.Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism.Conclusion: These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.