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Triggering of Antitumor Activity Through Melanoma-specific Transduction of a Constitutively Active Tumor Necrosis Factor (TNF) R1 Chimeric Receptor in the Absence of TNF-¹

Department of Pathology, Section of General Pathology, University of Verona, 37134 Verona, Italy

Tumor necrosis factor- (TNF-) has been intensively studied because of the specific toxicity of this cytokine toward cells that undergo malignant transformation. However, its proinflammatory and immunoregulatory properties always represented a drawback to the TNF- administration in cancer therapy. In this study, we describe an adenovirus-based strategy in which the tumoricidal activity of TNF- can be selectively triggered to eradicate tumors without administering TNF-. This strategy might allow us to prevent TNF- effects on normal tissues and, therefore, to bypass its systemic toxic effects. We inserted the constitutively active version of the M_r 55,000 TNF receptor, which was shown previously (F. Bazzoni et al., Proc. Natl. Acad. Sci. USA, 92: 5376–5380, 1995) to be capable of killing cells upon expression in the absence of its ligand, into a replication-deficient adenovirus, and under the control of a melanoma-specific promoter/enhancer element. We show that, upon infection, the recombinant gene reaches high level of expression in melanoma cell lines and triggers apoptosis by activating the caspase cascade. Expression and function of this receptor is restricted to melanoma cell lines, because morphology, viability, and proliferation of other cell types exposed to the recombinant adenovirus infection are not affected. We show for the first time that a TNF-like apoptotic response can be triggered in the absence of TNF- and can be selectively confined to specific cellular targets. Killing activity and tissue specificity of the recombinant TNF receptor adenovirus, together with the advantage of triggering a TNF-like antitumor activity in the absence of TNF- itself, are ideal features for a vector that might be the choice for gene therapy aimed to eradicate malignant cells.