Pourquier Philippe
Université de Bordeaux, Institut Bergonié, France.
Bull Cancer. 2011 Nov;98(11):1237-51. doi: 10.1684/bdc.2011.1471.
With the approval of mechlorethamine by the FDA in 1949 for the treatment of hematologic malignancies, alkylating agents are the oldest class of anticancer agents. Even though their clinical use is far beyond the use of new targeted therapies, they still occupy a major place in specific indications and sometimes represent the unique option for the treatment of refractory diseases. Here, we are reviewing the major classes of alkylating agents and their mechanism of action, with a particular emphasis for the new generations of alkylating agents. As for most of the chemotherapeutic agents used in the clinic, these compounds are derived from natural sources. With a complex but original mechanism of action, they represent new interesting alternatives for the clinicians, especially for tumors that are resistant to conventional DNA damaging agents. We also briefly describe the different strategies that have been or are currently developed to potentiate the use of classical alkylating agents, especially the inhibition of pathways that are involved in the repair of DNA lesions induced by these agents. In this line, the development of PARP inhibitors is a striking example of the recent regain of interest towards the "old" alkylating agents.
1949年美法仑获美国食品药品监督管理局（FDA）批准用于治疗血液系统恶性肿瘤，烷化剂是最古老的一类抗癌药物。尽管它们的临床应用范围远超新型靶向治疗药物，但在特定适应症中仍占据主要地位，有时还是治疗难治性疾病的唯一选择。在此，我们将回顾烷化剂的主要类别及其作用机制，尤其着重介绍新一代烷化剂。与临床使用的大多数化疗药物一样，这些化合物均来源于天然产物。它们具有复杂而独特的作用机制，为临床医生提供了新的有趣选择，特别是对于那些对传统DNA损伤剂耐药的肿瘤。我们还简要描述了过去或目前为增强经典烷化剂的使用而开发的不同策略，尤其是抑制这些药物诱导的DNA损伤修复途径。在这方面，聚（ADP - 核糖）聚合酶（PARP）抑制剂的开发就是近期重新关注“老”烷化剂的一个显著例子。
