DMXAA: An antivascular agent with multiple host responses
DMXAA: An antivascular agent with multiple host responses
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DOI：
10.1016/s0360-3016(02)03920-2
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发表时间：
2002-12-01
影响因子：
7
通讯作者：
Ching, LM
中科院分区：
文献类型：
--
作者：
Baguley, BC;Ching, LM
目的：观察宿主对抗血管药物DMXAA（5,6-二甲基杂蒽酮-4-乙酸）的反应，并与其他抗血管药物进行比较。方法：观察正常小鼠结肠癌和肿瘤坏死因子（TNF）受体-1敲除小鼠结肠癌对肿瘤坏死的诱导作用。ELISA法测定血浆及肿瘤组织TNF浓度。用高效液相色谱法测定血浆5-羟基吲哚乙酸（血清素释放的量度）和亚硝酸盐（一氧化氮释放的量度）的浓度。结果：荷瘤小鼠DMXAA除增加血浆一氧化氮外，还增加了血浆和肿瘤组织相关的TNF，其作用与具有抗血管作用的有丝分裂毒素不同。TNF受体-1敲除小鼠的结果显示TNF在抗肿瘤作用和宿主毒性方面都发挥了重要作用。血清素的释放是对有丝分裂中毒和DMXAA的反应。结论：DMXAA的抗血管作用涉及肿瘤组织中一系列血管活性事件的原位产生，包括对血管内皮细胞的直接作用和涉及TNF、其他细胞因子、血清素和一氧化氮的间接血管作用。现在DMXAA的I期临床试验已经完成，优化这种级联在癌症患者中的作用是一项重大挑战。血浆5-羟基吲哚乙酸浓度可作为DMXAA等抗血管药物抗血管作用的替代指标。(C) 2002爱思唯尔科学有限公司
Purpose: To measure host responses to the antivascular agent DMXAA (5,6-dimethylxanthenone-4-acetic acid) and to compare them with those of other antivascular agents.Methods: Induction of tumor necrosis was measured in s.c. murine Colon 38 carcinomas growing in normal or tumor necrosis factor (TNF) receptor-1 knockout mice. Plasma and tumor tissue TNF concentrations were measured by ELISA. Plasma concentrations of 5-hydroxyindoleacetic acid (as a measure of serotonin release) and nitrite (as a measure of nitric oxide release) were measured by high-performance liquid chromatography.Results: Administration of DMXAA to tumor-bearing mice increased plasma and tumor tissue-associated TNF, in addition to increasing plasma nitric oxide, distinguishing its action from that of mitotic poisons that had an antivascular action. Results from TNF receptor-1 knockout mice showed that TNF played an important role in both its antitumor action and its host toxicity. Release of serotonin occurred in response to mitotic poisons, as well as to DMXAA.Conclusions: The antivascular action of DMXAA involves in situ production in tumor tissue of a cascade of vasoactive events, including a direct effect on vascular endothelial cells and indirect vascular effects involving TNF, other cytokines, serotonin, and nitric oxide. Now that Phase I clinical trials of DMXAA are completed, the optimization of this cascade in cancer patients is a major challenge. Plasma 5-hydroxyindoleacetic acid concentrations may provide a useful surrogate marker for the antivascular effects of DMXAA and other antivascular agents. (C) 2002 Elsevier Science Inc.