Watts M E, Arnold S, Chaplin D J
Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK.
Br J Cancer Suppl. 1996 Jul;27:S164-7.
5,6 dimethyl xanthenone acetic acid (5,6 MeXAA), an analogue of flavone acetic acid (FAA), has been shown to be more active against murine tumours than FAA. As both drugs have a vascular component in their mechanism of action similar to that observed for TNF-alpha, we have studied the effects of 5,6 MeXAA alone and in combination with TNF-alpha on endothelial function in vitro. The changes induced by the drugs on procoagulant activity and permeability were determined under tumour-simulated conditions of low oxygen tension and the presence of tumour-secreted factors. Procoagulant activity was assayed by measuring the time taken for human umbilical vein endothelial cells (HUVECs) to clot normal human plasma, increased activity resulting in reduced clotting times. HUVECs incubated under aerobic conditions were more sensitive to TNF-alpha than cells incubated at < or = 0.2% oxygen. Culture medium conditioned by the human breast adenocarcinoma cell line MDA-MB-231 strongly upregulated procoagulant activity under both aerobic and hypoxic conditions; clotting times were further reduced by TNF-alpha. Both 5,6 MeXAA and FAA potentiated the effect of TNF-alpha on normal hypoxic endothelial cells; however, under all other conditions, neither drug in combination with TNF-alpha upregulated clotting activity. The presence of tumour-secreted factors had a far greater effect on upregulating procoagulant activity than did oxygen tension. In contrast to procoagulant activity, permeability was insensitive to TNF-alpha and low concentrations of 5,6 MeXAA also caused no change in permeability.
5,6-二甲基呫吨酮乙酸（5,6 MeXAA）是黄酮乙酸（FAA）的类似物，已证明其对鼠肿瘤的活性比FAA更强。由于这两种药物在作用机制中都有类似于肿瘤坏死因子-α（TNF-α）的血管成分，我们研究了单独使用5,6 MeXAA以及它与TNF-α联合使用对体外内皮功能的影响。在低氧张力和存在肿瘤分泌因子的肿瘤模拟条件下，测定药物诱导的促凝血活性和通透性变化。通过测量人脐静脉内皮细胞（HUVECs）使正常人血浆凝固所需的时间来测定促凝血活性，活性增加导致凝血时间缩短。在有氧条件下培养的HUVECs比在氧含量≤0.2%条件下培养的细胞对TNF-α更敏感。人乳腺腺癌细胞系MDA-MB-231条件培养液在有氧和缺氧条件下均强烈上调促凝血活性；TNF-α进一步缩短凝血时间。5,6 MeXAA和FAA均增强了TNF-α对正常缺氧内皮细胞的作用；然而，在所有其他条件下，这两种药物与TNF-α联合使用均未上调凝血活性。肿瘤分泌因子的存在对上调促凝血活性的影响远大于氧张力。与促凝血活性相反，通透性对TNF-α不敏感，低浓度的5,6 MeXAA也不会引起通透性变化。
