Mechanism of Action: The Unique Pattern of Bendamustine-Induced Cytotoxicity
Mechanism of Action: The Unique Pattern of Bendamustine-Induced Cytotoxicity
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DOI：
10.1053/j.seminhematol.2011.03.003
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发表时间：
2011-04-01
影响因子：
3.6
通讯作者：
Hartley, John A.
中科院分区：
文献类型：
--
作者：
Leoni, Lorenzo M.;Hartley, John A.
苯达莫司汀在血液恶性肿瘤的治疗中表现出显著的疗效，并且在肿瘤细胞中的活性方面继续将其与其他烷化剂区分开来。与苯达莫司汀相关的机制和临床差异可能与其独特的结构特征直接相关。虽然确切的作用机制仍然知之甚少，但苯达莫司汀与广泛和持久的DNA损伤有关。苯达莫司汀的效力增加可能是由于次级机制，如抑制有丝分裂检查点，DNA修复效率低下，并启动p53依赖性DNA损伤应激反应，所有这些都导致有丝分裂灾难和细胞凋亡。还假设除了氮芥基团之外，苯并咪唑环的存在可能影响苯达莫司汀与DNA相互作用的方式和/或赋予抗代谢物性质。进一步阐明苯达莫司汀的作用机制和参与苯达莫司汀诱导的DNA损伤反应的信号通路对于最大限度地发挥其治疗潜力、鉴定反应生物标志物以及了解与参与DNA损伤和抑制DNA修复的其他药物协同作用的潜力至关重要。本综述将讨论目前的理解和假设苯达莫司汀的作用机制，并建议未来的调查，将阐明许多悬而未决的问题。血液学研讨会48：S12-S23。(C)2011 Elsevier Inc. All rights reserved.
Bendamustine has demonstrated substantial efficacy in the treatment of hematologic malignancies and continues to distinguish itself from other alkylating agents with regard to its activity in tumor cells. The mechanistic and clinical differences associated with bendamustine may be directly related to its unique structural features. Although the precise mechanisms of action are still poorly understood, bendamustine is associated with extensive and durable DNA damage. The increased potency of bendamustine may be due to secondary mechanisms such as inhibition of mitotic checkpoints, inefficient DNA repair, and initiation of p53-dependent DNA-damage stress response, all of which lead to mitotic catastrophe and apoptosis. It has also been hypothesized that the presence of a benzimidazole ring in addition to the nitrogen mustard group may influence the way bendamustine interacts with DNA and/or confer antimetabolite properties. Further elucidation of the mechanisms of action for bendamustine and the signaling pathways involved in the response to bendamustine-induced DNA damage is essential to maximize its therapeutic potential, identify biomarkers for response, and understand the potential for synergy with other agents involved in DNA damage and inhibition of DNA repair. This review will discuss the current understanding and hypotheses regarding bendamustine mechanisms of action and suggest future investigations that would shed light on the many unanswered questions. Semin Hematol 48:S12-S23. (C) 2011 Elsevier Inc. All rights reserved.