IFN-β-dependent inhibition of tumor growth by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)
IFN-β-dependent inhibition of tumor growth by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)
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DOI：
10.1089/jir.2007.0992
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发表时间：
2008-03-01
影响因子：
2.3
通讯作者：
Vogel, Stefanie N.
中科院分区：
文献类型：
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作者：
Roberts, Zachary J.;Ching, Lai-Ming;Vogel, Stefanie N.
通过攻击已建立的肿瘤脉管系统，血管阻断剂（VDA）代表了治疗癌症的替代方法。一种这样的VDA，5，6-二甲基咕吨酮-4-乙酸（DMXAA），计划用于前列腺癌和肺癌与常规化疗联合的III期试验。在这项工作中，我们确定干扰素-β（IFN-β）作为一个中央调解人在主机的响应DMXAA。在携带刘易斯肺腺癌的小鼠中，单次腹膜内给药DMXAA显示出在野生型小鼠中肿瘤生长速率的高度显著降低，这在IFN-β缺失小鼠中没有观察到。此外，肿瘤内细胞因子表达显示依赖于宿主来源的IFN-β，因为DMXAA处理的IFN-β- null小鼠证明在切除的肿瘤组织中不仅缺乏IFN-β的诱导，而且缺乏抗血管生成细胞因子IP-10的诱导。这些结果支持以下结论：DMXAA部分通过宿主衍生元件诱导IFN-β表达获得其有效的抗癌特性。
By attacking established tumor vasculature, vascular disrupting agents (VDAs) represent an alternative approach to the treatment of cancer. One such VDA, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), is scheduled for phase III trials for prostate and lung cancer in combination with conventional chemotherapies. In this work, we identify interferon-beta (IFN-beta) as a central mediator in the host's response to DMXAA. In mice bearing Lewis lung adenocarcinomas, a single intraperitoneal dose of DMXAA was shown to effect a highly significant reduction in tumor growth rate in wild-type mice that was not seen in IFN-beta-null mice. Moreover, intratumoral cytokine expression was shown to be dependent on host-derived IFN-beta, as DMXAA-treated IFN-beta- null mice demonstrated a lack of induction of not only IFN-beta but also the antiangiogenic cytokine, IP-10, in excised tumor tissue. These results support the conclusion that DMXAA derives its potent anticancer properties in part through elicitation of IFN-beta expression by host-derived elements.