Augmentation of antitumor effect of endogenously induced tumor necrosis factor by cyclophosphamide

The antitumor effect of endogenous tumor necrosis factor (en-TNF) with cyclophosphamide (CY) was analyzed using the murine Meth A tumor model. En-TNF was induced by the administration of interferon-gamma (4 micrograms/kg: 1 x 10(4) units/ mouse) as a primer and Streptococcus preparation OK-432 (100 KE/kg) as a trigger. Seven days after inoculation of Meth A tumor in BALB/c mice, about one third of LD50 of CY or five other chemotherapeutic agents (actinomycin D, mitomycin C, tegaful, adriamycin and puromycin) was injected intravenously. En-TNF was induced 7 days after administration of these agents. A combination therapy of en-TNF with CY showed the strongest antitumor effect among several combinations and caused complete tumor regression (40-70%), while none of the combinations with the other chemotherapeutics did so. The optimal time interval to obtain this antitumor effect with CY and en-TNF induction was 7 days. The amount of en-TNF induced around a tumor lesion with CY was two fold higher than that without CY. En-TNF was observed to be induced in tumor lesion solely by CY injection. All these results suggest that the antitumor effect of en-TNF can be augmented by addition of a chemotherapeutic agent such as CY.