Changes in coagulation and permeability properties of human endothelial cells in vitro induced by TNF-alpha or 5,6 MeXAA.
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.
Watts
M E
ME
Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK.
Arnold
S
S
Chaplin
D J
DJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014966:Xanthenes / Q000494:pharmacology*; D044004:Xanthones
D000970:Antineoplastic Agents; D005419:Flavonoids; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; C049328:flavone acetic acid