Impact of tolerance on antitumor efficacy of tumor necrosis factor in mice

Repetitive sublethal doses of tumor necrosis factor (TNF) can induce tolerance or tachyphylaxis to the toxic effects of TNF. Because tumor-bearing (TB) mice are more sensitive to the toxic effects of TNF, this study investigates whether similar tolerance occurs in TB mice and whether it affects the antitumor response of TNF. Nontumor-bearing C3H/Hen mice were treated with twice daily i.p. sublethal escalating doses of human recombinant TNF (2, 2, 3, 3, 4, and 4 micrograms i.p. every 12 h for 6 days) and were challenged 2 days later with a lethal i.v. dose (40 micrograms) of TNF. TNF-pretreated mice had 100% survival as compared to 0% survival in control mice previously treated with saline (P less than 0.01). Tumor-bearing C57BL/6 mice bearing an MCA-106 or MCA-102 sarcoma were treated with an identical TNF-tolerizing regimen (2, 2, 3, 3, 4, and 4 micrograms i.p. every 12 h for 6 days) beginning 3 days following tumor inoculation and were similarly more resistant to a subsequent 100% lethal i.v. treatment dose of TNF than control TB mice. A significantly greater percentage of TNF-pretreated mice bearing the MCA-106 sarcoma survived treatment doses of 8, 12, and 16 micrograms of TNF i.v. than control TB mice. Similarly, a significantly greater percentage of TNF-pretreated mice bearing the MCA-102 sarcoma survived treatment doses of 6 and 9 micrograms of TNF i.v. than control TB mice. However, the ability to administer higher doses of TNF i.v. to TNF-pretreated TB mice did not improve therapeutic efficacy. In mice bearing the MCA-106 tumor the most efficacious treatment responses were seen in animals that were previously naive to TNF, and treatment toxicity (lethality) correlated directly with antitumor efficacy such that larger treatment doses of TNF in tolerant mice resulted in similar antitumor effects as smaller treatment doses in control TB mice. In mice bearing the MCA-102 tumor, equitoxic treatment doses of TNF produced similar antitumor effects in both control and tolerant TB mice. There were no differences in cure rate for TNF-tolerant or control TB mice bearing either tumor. The results suggest that TNF tolerance occurs in TB mice and reduces the toxicity as well as the therapeutic efficacy of TNF.