PMID- 19090007
OWN - NLM
STAT- MEDLINE
DCOM- 20090310
LR  - 20220129
IS  - 0008-543X (Print)
IS  - 1097-0142 (Electronic)
IS  - 0008-543X (Linking)
VI  - 115
IP  - 1
DP  - 2009 Jan 1
TI  - Tumor vasculature-targeted delivery of tumor necrosis factor-alpha.
PG  - 128-39
LID - 10.1002/cncr.24001 [doi]
AB  - BACKGROUND: Recently, considerable efforts have been directed toward antivascular 
      therapy as a new modality to treat human cancers. However, targeting a 
      therapeutic gene of interest to the tumor vasculature with minimal toxicity to 
      other tissues remains the objective of antivascular gene therapy. Tumor necrosis 
      factor-alpha (TNF-alpha) is a potent antivascular agent but has limited clinical 
      utility because of significant systemic toxicity. At the maximum tolerated doses 
      of systemic TNF-alpha, there is no meaningful antitumor activity. Hence, the 
      objective of this study was to deliver TNF-alpha targeted to tumor vasculature by 
      systemic delivery to examine its antitumor activity. METHODS: A hybrid 
      adeno-associated virus phage vector (AAVP) was used that targets tumor 
      endothelium to express TNF-alpha (AAVP-TNF-alpha). The activity of AAVP-TNF-alpha 
      was analyzed in various in vitro and in vivo settings using a human melanoma 
      tumor model. RESULTS: In vitro, AAVP-TNF-alpha infection of human melanoma cells 
      resulted in high levels of TNF-alpha expression. Systemic administration of 
      targeted AAVP-TNF-alpha to melanoma xenografts in mice produced the specific 
      delivery of virus to tumor vasculature. In contrast, the nontargeted vector did 
      not target to tumor vasculature. Targeted AAVP delivery resulted in expression of 
      TNF-alpha, induction of apoptosis in tumor vessels, and significant inhibition of 
      tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: 
      Targeted AAVP vectors can be used to deliver TNF-alpha specifically to tumor 
      vasculature, potentially reducing its systemic toxicity. Because TNF-alpha is a 
      promising antivascular agent that currently is limited by its toxicity, the 
      current results suggest the potential for clinical translation of this strategy.
FAU - Tandle, Anita
AU  - Tandle A
AD  - Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
FAU - Hanna, Engy
AU  - Hanna E
FAU - Lorang, Dominique
AU  - Lorang D
FAU - Hajitou, Amin
AU  - Hajitou A
FAU - Moya, Catherine A
AU  - Moya CA
FAU - Pasqualini, Renata
AU  - Pasqualini R
FAU - Arap, Wadih
AU  - Arap W
FAU - Adem, Asha
AU  - Adem A
FAU - Starker, Elizabeth
AU  - Starker E
FAU - Hewitt, Stephen
AU  - Hewitt S
FAU - Libutti, Steven K
AU  - Libutti SK
LA  - eng
GR  - G0701159/MRC_/Medical Research Council/United Kingdom
GR  - Z01 SC010368/ImNIH/Intramural NIH HHS/United States
GR  - ZIC BC011638/ImNIH/Intramural NIH HHS/United States
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Dependovirus/genetics
MH  - Gene Expression
MH  - Genetic Therapy/methods
MH  - Genetic Vectors
MH  - Humans
MH  - Melanoma/*blood supply/*therapy
MH  - Melanoma, Experimental/blood supply/therapy
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - Skin Neoplasms/*blood supply/*therapy
MH  - Transduction, Genetic
MH  - Tumor Necrosis Factor-alpha/*genetics/metabolism
PMC - PMC8385542
MID - NIHMS1728873
EDAT- 2008/12/18 09:00
MHDA- 2009/03/11 09:00
PMCR- 2021/08/25
CRDT- 2008/12/18 09:00
PHST- 2008/12/18 09:00 [entrez]
PHST- 2008/12/18 09:00 [pubmed]
PHST- 2009/03/11 09:00 [medline]
PHST- 2021/08/25 00:00 [pmc-release]
AID - 10.1002/cncr.24001 [doi]
PST - ppublish
SO  - Cancer. 2009 Jan 1;115(1):128-39. doi: 10.1002/cncr.24001.