The University of Auckland, Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, Private Bag 92019, Auckland, New Zealand.
Expert Opin Investig Drugs. 2010 Nov;19(11):1413-25. doi: 10.1517/13543784.2010.529128.
Tumor vascular disrupting agents (tumor VDAs) act by selective induction of tumor vascular failure. While their action is distinct from that of antiangiogenic agents, their clinical potential is likely to reside in improving the efficacy of combination therapy.
This review describes the preclinical development, clinical trial and mode of action of ASA404, a flavonoid class tumor VDA. This class has a unique dual action, simultaneously disrupting vascular endothelial function and stimulating innate tumor immunity. This review covers the early development of ASA404, through to Phase III trial.
The reader will gain insight into the sequence of ASA404-induced changes in tumor tissue. Early events include increased vascular permeability, increased endothelial apoptosis and decreased blood flow, while later effects include the induction of serotonin, tumor necrosis factor, other cytokines and chemokines, and nitric oxide. This cascade of events induces sustained reduction of tumor blood flow, induction of tumor hypoxia and increased inflammatory responses. The reader will also gain an appreciation of how the potentiation of radiation and chemotherapeutic effects by ASA404 in murine tumors shaped the development of combination clinical trials.
Although there are species differences in ASA404 activity, many features of its action in mice translate to human studies. The future of ASA404 as an effective clinical agent will rely on the development of an appreciation of its ability to optimize the complex interaction between tumor vasculature and tumor immunity during therapy.
肿瘤血管破坏剂（tumor VDAs）通过选择性诱导肿瘤血管衰竭起作用。虽然它们的作用与抗血管生成剂不同，但它们的临床潜力可能在于提高联合治疗的疗效。
本文综述了黄酮类肿瘤血管破坏剂 ASA404 的临床前开发、临床试验和作用机制。这一类药物具有独特的双重作用，既能破坏血管内皮功能，又能刺激固有肿瘤免疫。这篇综述涵盖了 ASA404 的早期开发，直至 III 期临床试验。
读者将深入了解 ASA404 诱导的肿瘤组织变化的顺序。早期事件包括血管通透性增加、内皮细胞凋亡增加和血流量减少，而后期效应包括 5-羟色胺、肿瘤坏死因子、其他细胞因子和趋化因子以及一氧化氮的诱导。这一连串的事件会导致肿瘤血流量持续减少、肿瘤缺氧和炎症反应增加。读者还将了解到 ASA404 如何增强辐射和化疗对小鼠肿瘤的疗效，从而为联合临床试验的发展提供了思路。
尽管 ASA404 在不同物种中的活性存在差异，但它在小鼠中的许多作用特征都可以转化为人类研究。ASA404 作为一种有效的临床药物的未来将取决于对其在治疗过程中优化肿瘤血管和肿瘤免疫之间复杂相互作用的能力的理解。
