A NOVEL TUMOR-DERIVED MEDIATOR THAT SENSITIZES CYTOKINE-RESISTANT TUMORS TO TUMOR-NECROSIS-FACTOR

Therapeutic successes following treatment of murine tumors with tumor necrosis factor-alpha (TNF) have not been easily applied to clinical o ncology because the concentrations of TNF required in humans induces s ystemic toxicity. This has led us to identify mediators which could se nsitize tumors to the effects of TNF, permitting administration of low er doses and possible realization of the therapeutic potential of this cytokine. Our study reports the ability of a novel cytokine, endothel ial-monocyte-activating polypeptide II (EMAP II), to sensitize initial ly resistant murine and human tumors to TNF-induced regression employi ng a murine model. Recombinant (r) EMAP II was purified from Escherich ia coli transformed with a plasmid expressing mature EMAP II. The B16 melanoma, raised in C57BL/6 mice, or a human fibrosarcoma (HT-1080), g rown in immunocompromised mice, was injected intratumorally with eithe r vehicle or rEMAP II/heat-treated EMAP II (50-100 mu g) followed by s ystemic TNF/heat-treated TNF (5 mu g) and assessed for tumor volume, h emorrhage, and histologic appearance. Both the B16 melanoma and the HT -1080 human fibrosarcoma underwent thrombohemorrhagic and acute inflam matory changes concomitant with regression or significantly slowed gro wth after administration of intratumor EMAP II followed by systemic TN F. Omission or inactivation of either cytokine abrogated this effect. These results demonstrate that local treatment of certain tumors with EMAP II results in enhanced susceptibility to TNF-mediated induction o f thrombohemorrhage and regression. (C) 1996 Academic Press, Inc.