EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA ON VASCULAR-RESISTANCE, NITRIC-OXIDE PRODUCTION, AND GLUCOSE AND OXYGEN-CONSUMPTION IN PERFUSED TISSUE-ISOLATED HUMAN-MELANOMA XENOGRAFTS

The effect of tumor necrosis factor alpha (TNF-alpha) on vascular resi stance, nitric oxide production, and consumption of oxygen and glucose was examined in a perfused tissue-isolated tumor model in nude mice, One experimental group was perfused with heparinized Krebs-Henseleit b uffer, a second orle was perfused with TNF-alpha (2 mu g/ml), and a th ird one was given an i.v. injection of TNF-alpha (500 mu g/kg) 5 h bef ore perfusion. The vascular resistance increased significantly 5 h aft er TNF-alpha injection. The increase in vascular resistance did not se em to be mediated by a decrease in tumor nitric oxide production, as d etermined by perfusate nitrate/nitrite concentrations, but may be due to aggregation of leukocytes, platelets, and erythrocytes and/or endot helial swelling, There was no difference in oxygen and glucose consump tion among the three experimental groups, The oxygen consumption was l inearly dependent on the amount of available oxygen in the perfusate, whereas the glucose consumption was constant and independent of the gl ucose delivery rate, The present experiments provide new insights into physiological and metabolic mechanisms of action of TNF-alpha for opt imization of future treatment schedules involving TNF-alpha.