Virus-directed enzyme prodrug therapy using CB1954

The virus-directed enzyme prodrug therapy (VDEPT) anticancer '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-to xic prodrug to a cytotoxic agent. The prodrug 5-(aziridin-1-yl)-2,4 dinitro benzamide, CB1954, has been proposed for use in enzyme-prodrug gene therapy systems with the Escherichia coil enzyme nitroreductase (Ntr). Ntr convert s CB1954 to 2- and 4-hydroxylamino derivatives, whereupon the non-enzymatic reaction of the 4-hydroxylamino derivative with cellular thio- esters gene rates a potent cytotoxic bifunctional alkylating agent capable of cross-lin king DNA, Ntr delivery has been achieved in vitro using retroviral and aden oviral vectors and confirmed by immunocytochemical demonstration of Ntr exp ression. The Ntr-expressing cells have been shown to be sensitized to CB195 4 by up to 2000-fold. The Ntr-CB1954 system shows effective bystander killi ng 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 futur e promise of this gene therapy strategy.