Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Grafton, Auckland, New Zealand.
Cancer. 2010 Apr 15;116(8):1859-71. doi: 10.1002/cncr.24975.
The unique characteristics of tumor vasculature represent an attractive target that may be exploited by vascular-targeting anticancer agents. A promising strategy involves the selective disruption of established tumor blood vessels by tumor-vascular disrupting agents (tumor-VDAs), which exhibit antivascular activity, resulting in inhibition of tumor blood flow and extensive necrosis within the tumor core. The tumor-VDA class can be subdivided into flavonoid compounds, which are related to flavone acetic acid, and tubulin-binding compounds. ASA404, of the flavonoid class, is the most advanced tumor-VDA in clinical development and has been evaluated preclinically and in several phase 1 and phase 2 studies. Preclinical studies have demonstrated the selective apoptosis of tumor endothelial cells and the inhibition of tumor blood flow. Synergistic activity was observed with ASA404 and with several chemotherapeutic agents, particularly taxanes. In clinical trials, compared with chemotherapy alone, ASA404 was tolerated well and produced improved activity in patients with nonsmall cell lung cancer when combined with paclitaxel and carboplatin. Phase 3 clinical trials are ongoing. Selectively targeting established tumor vasculature with tumor-VDAs represents a promising and innovative approach to improving the efficacy of standard anticancer therapies.
肿瘤血管的独特特征代表了一个有吸引力的靶点，可以被血管靶向抗癌药物利用。一种很有前途的策略是通过肿瘤血管破坏剂（tumor-VDA）选择性地破坏已建立的肿瘤血管，肿瘤血管破坏剂具有抗血管生成活性，导致肿瘤血流抑制和肿瘤核心广泛坏死。肿瘤-VDA 类可进一步分为黄酮类化合物，与黄酮乙酸有关，和微管结合化合物。黄酮类的 ASA404 是临床开发中最先进的肿瘤-VDA，已在临床前和几项 1 期和 2 期研究中进行了评估。临床前研究表明肿瘤内皮细胞的选择性凋亡和肿瘤血流的抑制。与紫杉醇和卡铂联合使用时，观察到 ASA404 与几种化疗药物，特别是紫杉烷类药物具有协同活性。在临床试验中，与单独化疗相比，紫杉醇和卡铂联合应用时，ASA404 耐受性良好，在非小细胞肺癌患者中提高了疗效。正在进行 3 期临床试验。用肿瘤血管破坏剂选择性地靶向已建立的肿瘤血管是提高标准抗癌疗法疗效的一种有前途和创新的方法。
