title: Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway.
abstract: 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.
authors: Department of Oncology, ORCRB, University of Oxford, Old Road Campus, Headington, Oxford, OX3 7DQ, UK.
authors: Takahiro
authors: T
authors: Seki
authors: Fionnadh
authors: F
authors: Carroll
authors: Sam
authors: S
authors: Illingworth
authors: Nicky
authors: N
authors: Green
authors: Ryan
authors: R
authors: Cawood
authors: Houria
authors: H
authors: Bachtarzi
authors: Vladimir
authors: V
authors: Subr
authors: Kerry D
authors: KD
authors: Fisher
authors: Leonard W
authors: LW
authors: Seymour
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014771:Virion / Q000502:physiology*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D054460:rho-Associated Kinases