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Tumor cells produce endogenous vascular endothelial growth factor (VEGF), which sensitizes endothelial cells for systemically administered tumor necrosis factor \u03b1 (TNF \u03b1) and synergistically enhances the TNF\u2010induced expression of tissue factor. We have analyzed the pathways involved in the induction of tissue factor in human umbilical cord vein endothelial cells (HUVECs) after combined stimulation with TNF and VEGF. By using specific low molecular weight inhibitors, we demonstrated that protein kinase C (PKC), p44\/42 and p38 mitogen\u2010activated protein (MAP) kinases, and stress\u2010activated protein kinase (JNK) are essentially involved in the induction of tissue factor. In contrast, the application of wortmannin, an inhibitor of phosphatidylinositol 3 (PI3)\u2010kinase, led to strongly enhanced expression of tissue factor in TNF\u2010 and VEGF\u2010treated cells, implicating a negative regulatory role for PI3\u2010kinase. <jats:italic>In vivo<\/jats:italic>, the application of wortmannin promoted the formation of TNF\u2010induced hemorrhages and intratumoral necroses in murine meth A tumors. The co\u2010injection of wortmannin lowered the effective dose of applied TNF. Therefore, it is conceivable that the treatment of TNF\u2010sensitive tumors with a combination of TNF and wortmannin will ensure the selective damage of the tumor endothelium and minimize the risk of systemic toxicity of TNF. TNF\u2010treatment in combination with specific inhibition of PI3\u2010kinase is a novel concept in anti\u2010cancer therapy. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.11345","type":"journal-article","created":{"date-parts":[[2003,8,22]],"date-time":"2003-08-22T13:36:44Z","timestamp":1061559404000},"page":"30-37","source":"Crossref","is-referenced-by-count":6,"title":["Negative regulatory role of PI3\u2010Kinase in TNF\u2010induced tumor necrosis"],"prefix":"10.1002","volume":"107","author":[{"given":"Susanne","family":"Matschurat","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Blum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Mitnacht\u2010Kraus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry 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