Nitroreductase: A prodrug-activating enzyme for cancer gene therapy

Peter Searle, Ming-Jen Chen, L Hu, Paul Race, Andrew Lovering, Jane Grove, Chris Guise, Mansooreh Jaberipour, Nicholas James, Vivien Mautner, Lawrence Young, David Kerr, A Mountain, Scott White, Eva Hyde

Research output: Contribution to journalArticlepeer-review

88 Citations (Scopus)


1. The prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) is activated by Escherichia coli nitroreductase (NTR) to a potent DNA-crosslinking agent. 2. Virus-mediated expression of NTR in tumour cells sensitizes them to CB1954 in vitro and in vivo, providing the basis for a strategy of cancer gene therapy. 3. A phase I trial of CB1954 in cancer patients has been completed, documenting the pharmacokinetics and establishing an acceptable dose. Subsequent trials of the replication-defective adenovirus CTL102 in patients with resectable tumours have documented expression of NTR in injected colorectal liver metastases, hepatocellular carcinoma, head and neck cancer and prostate cancer. Trials combining CTL102 and CB1954 are underway. 4. An oncolytic (replication-competent) adenovirus vector allowed increased expression of NTR in vitro and in a mouse tumour model, resulting in a greater reduction in tumour growth when combined with CB1954 treatment. 5. Alternative prodrugs may eventually prove superior to CB1954; a nitroaryl phosphoramide mustard prodrug activated by NTR shows a greater therapeutic index than CB1954 in a human ovarian carcinoma. 6. The crystal structure of NTR provided the basis for site-directed mutagenesis, which has identified a number of mutants with improved kinetics of CB1954 activation. These can provide improved cell sensitization to CB1954. Combinations of these are being tested. 7. The basis for a positive selection for improved NTR variants has been demonstrated.
Original languageEnglish
Pages (from-to)811-816
Number of pages6
JournalClinical and Experimental Pharmacology and Physiology
Issue number11
Publication statusPublished - 1 Nov 2004


  • oncolytic viruses
  • gene therapy
  • CB1954
  • protein engineering
  • adenovirus
  • nitroreductase
  • clinical trial
  • Escherichia coli
  • bacteriophage lambda
  • prodrug
  • cancer


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