Tumor vasculature-targeted delivery of tumor necrosis factor-alpha.
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.
Tandle
Anita
A
Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Hanna
Engy
E
Lorang
Dominique
D
Hajitou
Amin
A
Moya
Catherine A
CA
Pasqualini
Renata
R
Arap
Wadih
W
Adem
Asha
A
Starker
Elizabeth
E
Hewitt
Stephen
S
Libutti
Steven K
SK
D000818:Animals; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D008545:Melanoma / Q000098:blood supply* / Q000628:therapy*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012878:Skin Neoplasms / Q000098:blood supply* / Q000628:therapy*; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha