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    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.

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    Authors
    Cowen, Rachel L.
    Williams, Judith C.
    Emery, Steve
    Blakey, David
    Darling, John L.
    Lowenstein, Pedro R.
    Castro, Maria G.
    Issue Date
    2002
    
    Metadata
    Show full item record
    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.
    Citation
    Cancer Gene Therapy, 9 (11): 897-907
    Publisher
    nature.com
    Journal
    Cancer Gene Therapy
    URI
    http://hdl.handle.net/2436/29772
    DOI
    10.1038/sj.cgt.7700514
    PubMed ID
    12386828
    Additional Links
    https://www.nature.com/articles/7700514
    Type
    Journal article
    Language
    en
    ISSN
    0929-1903
    ae974a485f413a2113503eed53cd6c53
    10.1038/sj.cgt.7700514
    Scopus Count
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