Enhanced Antitumor Effect of Recombinant Human Tumor Necrosis Factor in Combination with Recombinant Human Granulocyte Colony‐stimulating Factor in BALB/c Mice

The synergistic antitumor effect of tumor necrosis factor (TNF) and granulocyte colony‐stimulating factor (G‐CSF) was investigated. G‐CSF was administered subcutaneously to BALB/c mice inoculated with Meth‐A cells at a dose of 2.5 μg/day for 5 consecutive days. When TNF (1 × 10(3) U) was administered intravenously to mice which had been pretreated with G‐CSF, tumor growth showed a 74.1% inhibition 17 days after the tumor cell inoculation, compared to that of untreated mice. In this experiment, G‐CSF significantly (P<0.025) enhanced the antitumor effect of TNF. The in vitro cytotoxicity of TNF (10 U/ml) towards Meth‐A cells was increased about 5.2‐fold in the presence of neutrophils (E/T=50) as compared to the cytotoxicity obtained with TNF alone. A combination of TNF and G‐CSF (50 ng/ml) in the presence of neutrophils, resulted in a 2.1 times greater cytotoxicity against Meth‐A cells as compared to that obtained without G‐CSF. Significant augmenting effects of G‐CSF on superoxide (O(2)(−)) production by TNF‐stimulated neutrophils were observed. These observation suggest that the neutrophil plays an important role in the antitumor action of TNF on Meth‐A cells, and that the antitumor effect of TNF is enhanced by combination with G‐CSF.