Auckland Cancer Society Research Center, Faculty of Medical & Health Sciences, The University of Auckland, New Zealand.
Future Oncol. 2010 Oct;6(10):1537-43. doi: 10.2217/fon.10.122.
ASA404 (5,6-dimethylxanthenone-4-acetic acid) was developed as an analogue of flavone acetic acid and found to induce hemorrhagic necrosis of experimental tumors. ASA404 simultaneously targets at least two cell types - vascular endothelial cells and macrophages - within the tumor microenvironment. In murine tumors, ASA404 induces coordinated decreases in tumor blood flow, increases in vascular permeability and increases in vascular endothelial apoptosis, all occurring within 1 h of administration. Over a slightly longer time scale, ASA404 induces an increase in tumor concentrations of TNF and a number of other cytokines. Phase I clinical trials confirmed its vascular effects in humans and Phase II trials demonstrated its activity in combination with the cytotoxic agents carboplatin and paclitaxel. While the molecular target of its action is not yet identified, current results suggest that ASA404 has the potential to augment the antitumor effects of other agents in cancer treatment. Studies of changes in tumor tissue following treatment with ASA404 either alone or combined and other agents will provide new insights into the dynamics of the tumor microenvironment.
ASA404（5,6-二甲基黄嘌呤-4-乙酸）是作为黄酮乙酸类似物开发的，被发现能诱导实验性肿瘤出血性坏死。ASA404 同时针对肿瘤微环境中的至少两种细胞类型 - 血管内皮细胞和巨噬细胞。在鼠类肿瘤中，ASA404 在给药后 1 小时内诱导肿瘤血流量协调减少、血管通透性增加和血管内皮细胞凋亡增加。在稍长的时间尺度上，ASA404 诱导肿瘤中 TNF 和许多其他细胞因子的浓度增加。I 期临床试验证实了其在人类中的血管作用，II 期试验表明其与细胞毒剂卡铂和紫杉醇联合具有活性。虽然其作用的分子靶标尚未确定，但目前的结果表明，ASA404 有可能增强癌症治疗中其他药物的抗肿瘤作用。单独或联合使用 ASA404 以及其他药物治疗后肿瘤组织变化的研究将为肿瘤微环境的动态提供新的见解。
