Hyperthermic Enhancement of the Antitumor Effect of Natural Human Tumor Necrosis Factor‐α and ‐β: an in vitro and in vivo Study

A synergistic antitumor effect of natural human tumor necrosis factor‐β (TNF‐β) in combination with hyperthermia was found, in comparison with that of TNF‐α, using an in vitro antiproliferative assay on a human colon cancer cell line (RPMI4788) and an in vivo tumor growth inhibition assay on Meth A sarcoma cells. In vitro combined treatment with TNF‐β (10,000 U/ml) and hyperthermia (at 43° for 60 min) synergistically inhibited the proliferation of the cells. Combined effects of TNF‐α or natural human interferon‐α or ‐γ (IFN‐α, ‐γ) and hyperthermia were also examined, and furthermore, the combinations of TNFs and IFNs were examined in combination with hyperthermia at 42°; their antiproliferative effects were further augmented by hyperthermia. In vivo growth of Meth A sarcoma cells (5 × 10(5)), transplanted subcutaneously into BALB/c mice, was inhibited significantly (P<0.05) with the combination of TNF‐α or ‐β (2 × 10(5) U/mouse) and hyperthermia (at 43° for 60 min) as compared to either a single intravenous injection of TNF‐α or ‐β alone or the hyperthermia alone. The influence of TNF‐β and hyperthermia on the cell cycle was examined. Flow cytometric analysis showed that RPMI4788 cells treated with TNF‐α or ‐β accumulated in the S phase of the cell cycle, and that hyperthermia (at 42° for 60 min) alone had no influence on the cell cycle and did not augment the S phase accumulation of the cells treated with TNF‐α or ‐β.