Linked Life Data

17024230

Source:http://linkedlifedata.com/resource/pubmed/id/17024230

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2006-12-13
pubmed:abstractText
The success of cancer gene therapies requiring in vivo gene transfer is severely hampered by the low efficacy of gene transfer, which has been difficult to improve. We therefore established a novel strategy to increase the share of transduced cells post gene transfer. We hypothesized that in vivo selection of tumor cells transduced with a suicide gene effectively enriches these cells within a tumor, thus allowing for an increased bystander effect after the prodrug is given, leading to enhanced eradication of tumor cells. We reasoned that in vivo enrichment should be achieved by exploiting the metabolism of the suicide gene product. For this 'enrichment-eradication' strategy we chose a fusion gene of cytosine deaminase and uracil phosphoribosyl transferase. Positive selection (enrichment) was to be achieved by concurrently giving N-(phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine de novo synthesis, which leads to pyrimidine depletion-mediated death of non-transduced cells, and cytosine, to rescue fusion gene expressing cells via the pyrimidine salvage pathway. Negative selection (eradication) was to be induced by giving the prodrug 5-fluorocytosine. Indeed, murine NXS2 neuroblastoma cells transduced with the fusion gene were effectively enriched in vitro, leading to a near-complete bystander effect. In vivo enrichment-eradication of NXS2 cells led to decreased tumor growth. This proof-of-principle study shows that enrichment-eradication may compensate the effects of low in vivo gene transfer efficacy, a major obstacle in cancer gene therapy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0929-1903
pubmed:author
pubmed:issnType
Print
pubmed:volume
14
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
30-8
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Enriching suicide gene bearing tumor cells for an increased bystander effect.
pubmed:affiliation
University Children's Hospital, Ulm, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't