考布他汀A4类肿瘤血管破坏剂的研究进展

肿瘤血管破坏剂(VDA)是一类靶向肿瘤血管的抗肿瘤药物,能够快速、有选择地引发肿瘤组织内部既成血管的塌陷,阻断血液供应,从而引发肿瘤组织缺血性坏死。因此,VDA在治疗实体瘤方面具有很大的应用前景。其中,考布他汀A₄(CA4)疗效较好,但同时毒性较大。在寻找更特异性的VDA过程中,研究者合成了一系列CA4的类似物。本文分析了这些CA4类似物的结构,指出二芳基桥链的顺式构型为其特点,而且这些化合物与微管蛋白上的秋水仙碱作用位点结合,抑制微管蛋白的聚合。与传统抗肿瘤药物不同的是,CA4类VDA的抗肿瘤作用主要是通过选择性破坏肿瘤组织的血管系统实现的。同时,本文介绍了CA4类VDA的典型药物、影响CA4类VDA药效的肿瘤因素和宿主因素,以及为增强疗效和降低毒性作用而进行的联合用药情况。虽然CA4类VDA具有很大的应用前景,但目前还存在一些缺点,因而有必要继续寻找高效低毒的VDA,同时寻找可靠的生物标志物来指导VDA的临床用药也很有必要。

Recent advances of combretastatin A4-type vascular disrupting agents

Vascular disrupting agents (VDAs) are the anti-tumor drugs that target tumor vasculature. VDAs can rapidly and selectively damage the already established vessels in tumor and block blood supply, thus causing tumor ischemic necrosis. Therefore, VDAs have good prospects of application in treatment of solid tumor. As a VDA, combretastatin A₄ has recently garnered attention for its high-efficacy despite its high toxicity. A series of combretastatin A₄ analogues have been synthetized in the process of looking for more specific VDAs. Based on analysis of the structure of these analogues, this paper pointed out that cis configuration of the biaryl-bridged chain is the structure characteristic of combretastatin A₄-type VDA, which interacts with the colchicine-binding site of tubulin and inhibits tubulin polymerization. Unlike traditional antineoplastic drugs, the antitumor mechanism of combretastatin A₄-type VDA is mainly to destroy tumor vasculature selectively. Also, this paper introduced typical drugs of combretastatin A₄-type VDA, the tumor factors and host factors that affect efficacy, as well as combination therapies that can enhance curative effects and reduce side effects. However, there are still some problems. So it is necessary to study the risk-benefit ratio of VDAs and find reliable biomarkers to guide the clinical use of these drugs.