Induction of tolerance allows separation of lethal and antitumor activities of tumor necrosis factor in mice.

Multiple administration of sublethal doses of recombinant murine tumor necrosis factor (TNF), e.g., 2 micrograms i.p. twice daily for 4 to 6 consecutive days, produces tachyphylaxis to the anorectic effects of TNF and tolerance towards a lethal challenge with recombinant murine TNF. The objective of this study was to examine whether the antitumor efficacy of TNF was retained in mice made tolerant. We treated tolerant and nontolerant C57BL/6 mice bearing a syngeneic B16BL6 melanoma tumor with repeated administrations of recombinant murine TNF (5 to 12.5 micrograms/injection) alone or in combination with recombinant murine gamma-interferon (5,000 to 50,000 units/injection). When the paralesional administration route was used, the tolerance-inducing pretreatment protected mice against the lethal outcome of both the single and the combination treatments (100% versus 40% survival in the former case; 80% versus 0% survival in the latter case) and still allowed complete regression of the tumor. When the i.p. route of administration was used, the final outcome was less positive; nevertheless, a significant protection against the lethal effects of the treatment was achieved without reduction of the antitumor efficacy. It is concluded that the toxic and antitumor activities of TNF are not inevitably linked and that their separation is an achievable research and perhaps a clinical goal.