The antitumour agent 5,6-dimethylxanthenone-4-acetic acid acts in vitro on human mononuclear cells as a co-stimulator with other inducers of tumour necrosis factor
The antitumour agent 5,6-dimethylxanthenone-4-acetic acid acts in vitro on human mononuclear cells as a co-stimulator with other inducers of tumour necrosis factor
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DOI：
10.1016/s0959-8049(01)00210-6
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发表时间：
2001-10-01
影响因子：
8.4
通讯作者：
Baguley, BC
中科院分区：
文献类型：
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作者：
Philpott, M;Ching, LM;Baguley, BC
目前处于I期试验的5，6-二甲基咕吨酮-4-乙酸（DMXAA）显示出对具有已建立的脉管系统的可移植小鼠肿瘤的优异活性。细胞因子的诱导，特别是肿瘤坏死因子（TNF），似乎是其行动的关键。我们研究了DMXAA在培养的人外周血白细胞（HPBL）中的TNF诱导。8 h后通过酶联免疫吸附试验测定TNF，2 h后通过电泳迁移率变动试验（EMSA）测定NF-κ B诱导。DMXAA（800 μ g/ml）单独对TNF的产生没有影响，但增加了4倍，细菌脂多糖（LPS）诱导TNF的能力。先前报道的结果显示，单独使用DMXAA产生TNF，这可追溯到在较早批次的DMXAA中存在少量LPS，其作用可被多粘菌素B阻断。DMXAA刺激脱酰LPS产生TNF，单独作用不大。CD 14受体的抗体（MEM-18）在阻断LPS诱导TNF的同时，使DMXAA能够合成TNF并诱导NF-κ B。结构相关的药物黄酮乙酸（FAA）不诱导TNF或与抗CD 14抗体协同作用。DMXAA强烈增强了次优浓度的白细胞介素-1（IL-1）（25 ng/ml）、冈田酸（OA）（20 ng/ml）和佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA）（5 ng/ml）诱导TNF产生的能力，表明其影响汇聚于NF-κ B活化的多个途径。水杨酸钠是一种据报道抑制I κ B激酶（IKK）β亚基的药物，在抗CD 14抗体存在下似乎竞争性抑制DMXAA产生TNF。总之，结果表明DMXAA在体外作用于HPBL，通过多种试剂共刺激TNF产生，并表明IKK是介导该作用的靶点。(C)2001爱思唯尔科技有限公司版权所有。
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), currently in phase I trials, demonstrates excellent activity against transplantable murine tumours with established vasculature. The induction of cytokines, particularly of tumour necrosis factor (TNF), appears to be critical to its action. We investigated TNF induction by DMXAA in cultured human peripheral blood leucocytes (HPBL). TNF was measured by an enzyme-linked immunosorbent assay after 8 h, and NF-kappaB induction by electrophoretic mobility shift assays (EMSA) after 2 h. DMXAA (800 mug/ml) had no effect alone on TNF production but augmented, by up to 4-fold, the ability of bacterial lipopolysaccharide (LPS) to induce TNF. Previously reported results showing TNF production by DMXAA alone were traced to the presence in an earlier batch of DMXAA of a small amount of LPS, the action of which could be blocked by polymyxin B. DMXAA stimulated TNF production by deacylated LPS, which alone had little effect. An antibody (MEM-18) to the CD14 receptor, while blocking the induction of TNF by LPS, enabled DMXAA to both synthesise TNF and induce NF-kappaB. The structurally related drug, flavone acetic acid (FAA), did not induce TNF or synergise with anti-CD14 antibody. DMXAA strongly augmented the ability of suboptimal concentrations of interleukin-1 (IL-1) (25 ng/ml), okadaic acid (OA) (20 ng/ml) and phorbol-12-myristate-13-acetate (PMA) (5 ng/ml) to induce TNF production, suggesting that it affects multiple pathways converging on NF-kappaB activation. Sodium salicylate, a drug reported to inhibit the beta -subunit of I kappaB kinase (IKK), appeared to competitively inhibit TNF production by DMXAA in the presence of anti-CD14 antibody. Taken together, the results indicate DMXAA acts in vitro on HPBL to co-stimulate TNF production by a wide variety of agents, and suggests that IKK is the target that mediates this action. (C) 2001 Elsevier Science Ltd. All rights reserved.