PMID- 11221832
OWN - NLM
STAT- MEDLINE
DCOM- 20010315
LR  - 20081121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 61
IP  - 3
DP  - 2001 Feb 1
TI  - 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.
PG  - 1050-7
AB  - 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.
FAU - Bazzoni, F
AU  - Bazzoni F
AD  - Department of Pathology, University of Verona, Italy. Bazzon@borgoroma.univr.it
FAU - Regalia, E
AU  - Regalia E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antigens, CD)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 11096-26-7 (Erythropoietin)
RN  - EC 1.14.18.1 (Monophenol Monooxygenase)
SB  - IM
MH  - Adenoviridae/genetics/physiology
MH  - Animals
MH  - Antigens, CD/biosynthesis/genetics/*physiology
MH  - Apoptosis/physiology
MH  - Cell Division/physiology
MH  - Cell Line
MH  - Cell Survival/physiology
MH  - Enhancer Elements, Genetic
MH  - Erythropoietin/biosynthesis/genetics
MH  - Humans
MH  - Melanoma/enzymology/*genetics/pathology/therapy
MH  - Mice
MH  - Monophenol Monooxygenase/biosynthesis/genetics
MH  - Promoter Regions, Genetic
MH  - Receptors, Tumor Necrosis Factor/biosynthesis/genetics/*physiology
MH  - Receptors, Tumor Necrosis Factor, Type I
MH  - Recombinant Fusion Proteins/biosynthesis/genetics/*physiology
MH  - Signal Transduction/physiology
MH  - Transduction, Genetic
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/deficiency/*physiology
MH  - Virus Replication
EDAT- 2001/02/28 10:00
MHDA- 2001/03/17 10:01
CRDT- 2001/02/28 10:00
PHST- 2001/02/28 10:00 [pubmed]
PHST- 2001/03/17 10:01 [medline]
PHST- 2001/02/28 10:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2001 Feb 1;61(3):1050-7.