Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway

Tumour Necrosis Factor alpha (TNF) is a pleiotropic pro-inflammatory cytokine with known vascular permeabilising activity. It is employed during isolated limb perfusion to enhance delivery of chemotherapeutic drugs into tumour tissue. The use of conditionally-replicating lytic viruses, so called ‘on...

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Bibliographic Details
Published in:Journal of controlled release 2011-12, Vol.156 (3), p.381-389
Main Authors: Seki, Takahiro, Carroll, Fionnadh, Illingworth, Sam, Green, Nicky, Cawood, Ryan, Bachtarzi, Houria, Šubr, Vladimir, Fisher, Kerry D., Seymour, Leonard W.
Format: Article
Language:English
Subjects:
Adenoviridae - physiology
Adenovirus
albumins
Animals
Biological and medical sciences
Capillary Permeability - drug effects
Cell Line
Drug delivery
drug therapy
drugs
Endothelium, Vascular - drug effects
EPR-effect
General pharmacology
Humans
intravenous injection
Medical sciences
Mice
neoplasm cells
neoplasms
Neoplasms - therapy
Oncolytic Virotherapy - methods
Oncolytic Viruses - physiology
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
polymers
Rho A/Rho kinase inhibitor
rho-Associated Kinases - metabolism
Signal Transduction - drug effects
tumor necrosis factor-alpha
Tumor Necrosis Factor-alpha - pharmacology
Tumour necrosis factor-α
Vascular permeability
Virion - physiology
viruses
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Summary:Tumour Necrosis Factor alpha (TNF) is a pleiotropic pro-inflammatory cytokine with known vascular permeabilising activity. It is employed during isolated limb perfusion to enhance delivery of chemotherapeutic drugs into tumour tissue. The use of conditionally-replicating lytic viruses, so called ‘oncolytic virotherapy’, provides a new approach to cancer treatment that is currently limited by the low efficiency of extravasation of viral particles into tumours. We report here evidence that TNF significantly enhances the delivery of virus particles through the endothelial layer to allow access to tumour cells both in vitro and in vivo. Intravenous administration of TNF resulted in a 3- to 6-fold increase in EL4 tumour uptake of Evans Blue/Albumin, adenovirus and long-circulating polymer coated adenovirus. Interestingly, endothelial permeabilisation could be suppressed in vitro and in vivo by Y-27632, a Rho kinase inhibitor, without inhibiting viral infection. These data indicate that TNF can enhance the delivery of virus particles into tumours through a Rho A/Rho kinase dependent mechanism and may be a valuable strategy for increasing the delivery of oncolytic viruses and other therapeutic agents. [Display omitted]
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2011.08.022