Virus-detected enzyme prodrug therapy using CB1954: Ingenta Connect

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Affiliations: 1: Corresponding author address: CRC Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK 2: CRC Institute for Cancer Studies and 3: Department of Surgery, University of Birmingham, Birmingham B15 2TT, UK 4: Current address: ICRF Oncology Unit, Hammersmith Hospital, London, W12 0NN, UK The virus-directed enzyme prodrug therapy (VDEPT) anti-cancer ‘gene therapy’ strategy relies on the use of viral vectors for the efficient delivery to tumour cells of a ‘suicide gene’ encoding an enzyme which converts a non-toxic prodrug to a cytotoxic agent. The prodrug 5-(aziridin-1-yl)-2,4 dinitrobenzamide, CB1954, has been proposed for use in an enzyme-prodrug gene therapy system with the enzyme nitroreductase (Ntr). Ntr converts CB1954 to 2- and 4-hydroxylamino derivatives, whereupon the non-enzymatic reaction of the 4-hydroxylamino derivative with cellular thioesters generates a potent cytotoxic bifunctional alkylating agent capable of cross-linking DNA. Ntr delivery has been achieved using retroviral and adenoviral vectors and confirmed by immunocytochemical demonstration of Ntr expression. The Ntr-expressing cells have been shown to be sensitized to CB1954 by up to 2000-fold. The Ntr-CB1954 system shows effective bystander killing in mixed populations of Ntr-expressing and non-expressing cells treated with CB1954. The efficacy of this enzyme-prodrug approach in model systems compared with other VDEPT approaches demonstrates the feasibility and future promise of this gene therapy strategy. Corresponding author address: CRC Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK Source.

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