Triggering of antitumor activity through melanoma-specific transduction of a constitutively active tumor necrosis factor (TNF) R1 chimeric receptor in the absence of TNF-alpha.
Cancer Res
; 61(3): 1050-7, 2001 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-11221832
ABSTRACT
Tumor necrosis factor-alpha (TNF-alpha) 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-alpha administration in cancer therapy. In this study, we describe an adenovirus-based strategy in which the tumoricidal activity of TNF-alpha can be selectively triggered to eradicate tumors without administering TNF-alpha. This strategy might allow us to prevent TNF-alpha effects on normal tissues and, therefore, to bypass its systemic toxic effects. We inserted the constitutively active version of the Mr 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-alpha 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-alpha itself, are ideal features for a vector that might be the choice for gene therapy aimed to eradicate malignant cells.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Problema de saúde:
6_malignant_skin_melanoma
Assunto principal:
Proteínas Recombinantes de Fusão
/
Antígenos CD
/
Fator de Necrose Tumoral alfa
/
Receptores do Fator de Necrose Tumoral
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Melanoma
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
Itália