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Sensitization of Tumor Necrosis Factor -resistant Human Melanoma by Tumor-specific in Vivo Transfer of the Gene Encoding Endothelial Monocyte-activating Polypeptide II Using Recombinant Vaccinia Virus¹

Surgery Branch [M. F. X. G., A. C. B., J. H., M. P., P. C. W., D. L. B., H. R. A., S. K. L.] and Surgical Pathology Section [M. J. M.], National Cancer Institute, NIH, Bethesda, Maryland 20892; Department of Surgery, University of Vienna, A-1090 Vienna, Austria [M. F. X. G.]; and Department of Surgery, Technical University Munich, D-81675 Munich, Germany [M. P.]

Tumor necrosis factor (TNF-) is a proinflammatory cytokine with potent experimental antitumor activity. Its clinical use in cancer treatment is severely limited by its considerable toxicity after systemic administration, and it is currently confined to isolated limb and organ perfusion settings.

In this report, we introduce a novel concept of TNF--based gene therapy using the TNF-sensitizing properties of endothelial cell monocyte-activating polypeptide II (EMAP-II). We hypothesized that transfer of the EMAP-II gene into established TNF-resistant human melanomas would render these tumors sensitive to subsequent systemic TNF- treatment.

To achieve tumor selective gene delivery, we constructed a recombinant vaccinia virus encoding the human EMAP-II gene (vvEMAP). In vitro transfection of human melanoma cells led to the production of EMAP-II by these cells. Supernatants of vvEMAP-transfected tumor cells mediated the induction of tissue factor in endothelial cells.

We characterized the pattern of gene expression after systemic administration of a recombinant vaccinia virus encoding a reporter gene in a murine in vivo model of s.c. human melanoma. Gene expression in tumor tissue was increased 100-fold as compared with normal tissue, providing evidence for tumor-selective gene delivery.

Finally, human melanomas in nude mice were sensitized in vivo by transferring the EMAP-II gene using vvEMAP. Subsequent systemic administration of TNF- led to tumor regression and growth inhibition of these previously TNF-resistant tumors (P < 0.05).

This approach using gene therapy to sensitize primarily unresponsive tumors toward TNF- may enhance the usefulness of TNF- in clinical treatment strategies by increasing the window for the therapeutic application of the cytokine, thus reducing the dose necessary for antitumor responses and subsequently reduce toxicity.

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