Enhancement of Blood Stasis and Vascular Permeability in Meth-A Tumors by Administration of Hyperthermia in Combination with Tumor Necrosis Factor

Blood stasis and vascular permeability induced by tumor necrosis factor (TNF) in Meth-A tumors transplanted in BALB/c mice were significantly enhanced by hyperthermia at 40°C for 30 min immediately following TNF administration. A dose-dependent, sustained decline in the intratumoral blood flow rate occurred following the administration of TNF alone (i.v.; 5 × 10³, 5 × 10⁴, or 5 × 10⁵ JRU/kg) and was enhanced by the administration of hyperthermia in combination with the TNF, even though no decline occurred with hyperthermia alone. The combination of TNF at 5 × 10⁵ JRU/kg and hyperthermia resulted in a blood flow ratio (ratio of blood flow after administration to that before) of 0.47 at 1 h compared with a ratio of 0.65 at 1 h after TNF alone. The blood flow in normal skin sites did not decrease in any case. The permeability of the intratumoral vasculature similarly increased in a dose-dependent manner after the administration of TNF alone and was further increased by combination with hyperthermia, even though no increase occurred with hyperthermia alone. The mean permeability in mice receiving TNF alone at 5 × 10⁵ JRU/kg was 1.35 times that in untreated mice. In mice receiving TNF at the same dose together with hyperthermia, the ratio was increased to 1.65. The results suggest that TNF selectively suppresses intratumoral blood flow, that this effect is enhanced by mild hyperthermia, and that the mechanism of the suppression by TNF with or without hyperthermia partly involves an increase in blood vessel permeability.