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Wolverhampton Intellectual Repository and E-Theses > Research Institutes > Research Institute in Healthcare Science > Cancer Research Group > Adenovirus vector-mediated delivery of the prodrug-converting enzyme carboxypeptidase G2 in a secreted or GPI-anchored form: High-level expression of this active conditional cytotoxic enzyme at the plasma membrane.

Please use this identifier to cite or link to this item: http://hdl.handle.net/2436/29772
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Title: Adenovirus vector-mediated delivery of the prodrug-converting enzyme carboxypeptidase G2 in a secreted or GPI-anchored form: High-level expression of this active conditional cytotoxic enzyme at the plasma membrane.
Authors: Cowen, Rachel L.
Williams, Judith C.
Emery, Steve
Blakey, David
Darling, John L.
Lowenstein, Pedro R.
Castro, Maria G.
Citation: Cancer Gene Therapy, 9 (11): 897-907
Publisher: nature.com
Journal: Cancer Gene Therapy
Issue Date: 2002
URI: http://hdl.handle.net/2436/29772
DOI: 10.1038/sj.cgt.7700514
PubMed ID: 12386828
Additional Links: http://www.nature.com/cgt/journal/v9/n11/abs/7700514a.html
http://direct.bl.uk/bld/PlaceOrder.do?UIN=122740146&ETOC=RN&from=searchengine
Abstract: Carboxypeptidase G2 (CPG2) is a powerful prodrug-converting enzyme. Without a requirement for endogenous enzymes or cofactors, it can directly activate mustard alkylating prodrugs to cytotoxic species, killing both quiescent and dividing cells. This paper provides the first report of its use in the context of a clinically relevant delivery vehicle using adenovirus vectors. To strengthen the efficacy of the prodrug-activating system, the enzyme has been engineered to be secreted or glycosylphosphatidylinositol (GPI) anchored to the extracellular membrane of tumor cells, resulting in an enhanced bystander effect by facilitating diffusion of the active drug through extracellular, rather than intracellular, activation. Using the vectors, we have achieved expression of functional secreted or GPI-anchored CPG2 in a panel of tumor cell lines demonstrating no loss in efficacy as a result of GPI anchor retention. Despite variable transduction efficiencies inherent to these vectors, greater than 50% cell kill was achievable in all of the cell lines tested following only a single exposure to the prodrug ZD2767P. Even in cell lines refractive to infection with the vectors, substantial cell death was recorded, indicative of the enhanced bystander effect generated following extracellular prodrug activation. A direct evaluation of the efficacy of our system has been made against adenoviral delivery of herpes simples virus thymidine kinase plus ganciclovir (GCV), a suicide gene therapy approach already in the clinic. In a short-term human glioma culture (IN1760) resistant to the clinical chemotherapeutic drug CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea), thymidine kinase/GCV effected no cell killing compared to 70% cell killing with our system.
Type: Article
Language: en
Keywords: Suicide gene therapy
Carboxypeptidase G2
Chemosensitivity
GPI anchor
Oncology
Cancer treatment
MeSH: Adenoviridae
Amino Acid Sequence
Animals
Antigens, Thy-1
Base Sequence
Cell Membrane
Cell Survival
DNA Primers
Exons
Genetic Vectors
Glycosylphosphatidylinositols
Humans
Molecular Sequence Data
Mutagenesis, Site-Directed
Prodrugs
Rats
Recombinant Fusion Proteins
Transfection
Tumor Cells, Cultured
gamma-Glutamyl Hydrolase
ISSN: 0929-1903
Appears in Collections: Cancer Research Group

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