Antitumor activity of recombinant human tumor necrosis factor in combination with hyperthermia, chemotherapy, or immunotherapy.

The antitumor activity of recombinant human tumor necrosis factor (rhTNF) against methylcholanthrene A-induced sarcoma (Meth A sarcoma) and human tumors in vivo was studied. On systemic administration of rhTNF to Meth A sarcoma-bearing mice, tumor regression was achieved with a large dose or with repeated administration of a small dose. Strong antitumor activity could be achieved in the Meth A sarcoma model by administration of a small dose of rhTNF in combination with moderate temperature hyperthermia (p less than 0.005). rhTNF (1,000 U/mouse) combined with moderate hyperthermia (40 degrees C for 40 min) within 2 h after the TNF administration effected 100% complete regression. In contrast, the rhTNF or moderate hyperthermia alone revealed 0% complete regression. The antitumor activity of rhTNF was decreased in combination with cyclophosphamide (0.6 or 1.2 mg/mouse) (p less than 0.005). However, in combination with mitomycin C (30 or 120 micrograms/mouse), the antitumor activity of rhTNF was enhanced (p less than 0.005). In combination with immunotherapy (lentinan or OK 432), the antitumor activity was mostly enhanced. Repeated rhTNF administration also displayed antitumor activity in heterotransplanted human tumors (p less than 0.005). The antitumor activity of TNF was enhanced by repeated administration of even small dosages, in combination with hyperthermia, or in combination with immunotherapy.