Tumor necrosis factor: clinical use and mechanisms of action

Administration of high doses of TNF and IFN gamma by isolated limb perfusio n to patients affected by in transit melanoma metastases or inoperable soft tissue sarcoma of the limb, results in a high rate of complete response co mpared to chemotherapy alone. TNF/IFN gamma induce apoptosis of angiogenic endothelial cells and selectively disrupt the tumor vasculature. The study of the cellular and molecular events mediating this effect has revealed tha t TNF and IFN gamma inhibit the function of integrin alphaV beta3, an adhes ion receptor expressed on angiogenic endothelial cells and essential for th eir survival, resulting in impaired endothelial cell adhesion, spreading, f ocal adhesion formation and cell survival. These and other recent findings may open new perspectives in the clinical use of TNF as anti-tumor agent as well as in the design of new anti-vascular strategies aimed to disrupt the tumor vasculature. (C) 2000 Harcourt Publishers Ltd.