Anti-tumor effects of tumor necrosis factor in combination with chemotherapeutic agents

The anti-tumor activity of partially purified tumor necrosis factor (TNF) was analysed in combination with chemotherapeutic drugs against intradermally transplanted Meth A sarcoma. Tumors were allowed to grow until they reached an average diameter of about 8 mm. TNF was given once i.v. (16,000 units as determined on L-M cells) and the chemotherapeutic agents adriamycin (1-10 mg/kg), 5-FU (3-100 mg/kg), cyclophosphamide (50-200 mg/kg) were applied once i.p. 4 hr after TNF injection. The strongest anti-tumor effects in normal BALB/c mice were observed when TNF was combined with the following doses of chemotherapeutic agents: cyclophosphamide 100 mg/kg, adriamycin 5 mg/kg, 5-FU 30-100 mg/kg. The most effective combinations induced complete regressions. When TNF was combined with varying doses of adriamycin and cyclophosphamide, bell-shaped dose-response curves were obtained. Experiments were repeated in Meth A sarcoma-bearing BALB/c nu/nu mice. In this case TNF combinations with cyclophosphamide and 5-FU did not induce tumor regressions. The highest dose of the chemotherapeutic agent was the most effective in drug combinations. Histological analysis revealed a potentiation of the TNF-induced necrosis by cyclophosphamide. Increased hyperemia and extravasation of erythrocytes could be found in tumors of animals treated with the drug combination.