PMID- 19272140
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20100521
LR  - 20211020
IS  - 1479-0556 (Electronic)
IS  - 1479-0556 (Linking)
VI  - 7
DP  - 2009 Mar 9
TI  - Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours.
PG  - 5
LID - 10.1186/1479-0556-7-5 [doi]
AB  - The most common cause of death of cancer sufferers is through the occurrence of 
      metastases. The metastatic behaviour of tumour cells is regulated by 
      extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for 
      the c-Met receptor tyrosine kinase, and aberrant expression/activation of the 
      c-Met receptor is closely associated with metastatic progression. Nk4 (also known 
      as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and 
      inhibits c-Met signalling and tumour metastasis. Nk4 has an additional 
      anti-angiogenic activity independent of its HGF-antagonist function. 
      Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects 
      make the Nk4 sequence an attractive candidate for gene therapy of cancer. This 
      study investigates the inhibition of tumour metastasis by gene therapy mediated 
      production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is 
      vital in order to achieve the highest therapeutic responses. Non-viral plasmid 
      delivery methods have the advantage of safety and ease of production, providing 
      immediate transgene expression, albeit short-lived in most tumours. Sustained 
      presence of anti-angiogenic molecules is preferable with anti-angiogenic 
      therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) 
      might represent a more appropriate delivery in this respect. However, the 
      incubation time required by AAV vectors to reach appropriate gene expression 
      levels hampers efficacy in many fast-growing murine tumour models. Here, we 
      describe murine trials assessing the effects of Nk4 on the spontaneously 
      metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via 
      plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced 
      the highest therapeutic response with significant reduction in both primary 
      tumour growth and incidence of lung metastases. Plasmid-mediated therapy also 
      significantly reduced metastatic growth, but with moderate reduction in primary 
      subcutaneous tumour growth. Overall, this study demonstrates the potential for 
      Nk4 gene therapy of metastatic tumours, when delivered by AAV or non-viral 
      methods.
FAU - Buhles, Alexandra
AU  - Buhles A
AD  - Cork Cancer Research Centre, Mercy University Hospital, Leslie C Quick Junior 
      Laboratory, University College Cork, Cork, Ireland. alexandrabuhles@yahoo.com
FAU - Collins, Sara A
AU  - Collins SA
FAU - van Pijkeren, Jan P
AU  - van Pijkeren JP
FAU - Rajendran, Simon
AU  - Rajendran S
FAU - Miles, Michelle
AU  - Miles M
FAU - O'Sullivan, Gerald C
AU  - O'Sullivan GC
FAU - O'Hanlon, Deirdre M
AU  - O'Hanlon DM
FAU - Tangney, Mark
AU  - Tangney M
LA  - eng
PT  - Journal Article
DEP - 20090309
PL  - England
TA  - Genet Vaccines Ther
JT  - Genetic vaccines and therapy
JID - 101178414
PMC - PMC2669068
EDAT- 2009/03/11 09:00
MHDA- 2009/03/11 09:01
PMCR- 2009/03/09
CRDT- 2009/03/11 09:00
PHST- 2008/10/29 00:00 [received]
PHST- 2009/03/09 00:00 [accepted]
PHST- 2009/03/11 09:00 [entrez]
PHST- 2009/03/11 09:00 [pubmed]
PHST- 2009/03/11 09:01 [medline]
PHST- 2009/03/09 00:00 [pmc-release]
AID - 1479-0556-7-5 [pii]
AID - 10.1186/1479-0556-7-5 [doi]
PST - epublish
SO  - Genet Vaccines Ther. 2009 Mar 9;7:5. doi: 10.1186/1479-0556-7-5.