title: Virus-directed enzyme prodrug therapy using CB1954.
abstract: 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 enzyme-prodrug gene therapy systems with the Escherichia coli enzyme nitroreductase (Ntr). Ntr converts CB1954 to 2- and 4-hydroxylamino derivatives, whereupon the non-enzymatic reaction of the 4-hydroxylamino derivative with cellular thio- esters generates a potent cytotoxic bifunctional alkylating agent capable of cross-linking DNA. Ntr delivery has been achieved in vitro 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.
authors.affiliation: Cobra Therapeutics Ltd, The Science Park, Keele, Staffordshire, UK. groveji@cancer.bham.ac.uk
authors.forename: J I
authors.initials: JI
authors.lastname: Grove
authors.forename: P F
authors.initials: PF
authors.lastname: Searle
authors.forename: S J
authors.initials: SJ
authors.lastname: Weedon
authors.forename: N K
authors.initials: NK
authors.lastname: Green
authors.forename: I A
authors.initials: IA
authors.lastname: McNeish
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
mesh_terms: D000477:Alkylating Agents / Q000627:therapeutic use*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D001388:Aziridines / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D001711:Biotransformation; D015195:Drug Design; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D009601:Nitroreductases / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000627:therapeutic use*; D051381:Rats; D014780:Viruses / Q000235:genetics*
chemical_list: D000477:Alkylating Agents; D018906:Antineoplastic Agents, Alkylating; D001388:Aziridines; D011355:Prodrugs; C100099:tretazicar; D009601:Nitroreductases