Virus-directed enzyme prodrug therapy using CB1954

Anticancer Drug Des. 1999 Dec;14(6):461-72.


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.

Publication types

  • Review

MeSH terms

  • Alkylating Agents / therapeutic use*
  • Animals
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / metabolism
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Aziridines / administration & dosage
  • Aziridines / metabolism
  • Aziridines / therapeutic use*
  • Biotransformation
  • Drug Design
  • Genetic Therapy / methods*
  • Genetic Vectors / therapeutic use*
  • Humans
  • Mice
  • Nitroreductases / genetics
  • Nitroreductases / metabolism
  • Prodrugs / therapeutic use*
  • Rats
  • Viruses / genetics*


  • Alkylating Agents
  • Antineoplastic Agents, Alkylating
  • Aziridines
  • Prodrugs
  • tretazicar
  • Nitroreductases