This programme seeks to develop novel strategies for cancer therapy through selective activation of prodrugs within tumours. The major emphasis is on killing chemo- and radio-resistant hypoxic cells, and thereby exploiting what is arguably the best validated therapeutic target in oncology yet to be successfully utilised in the clinic. In addition, we seek to activate prodrugs selectively within tumours through delivery of prodrug-activating enzymes (bacterial nitroreductases) using tumour-tropic conditionally replicating adenoviruses. The programme stemmed from our discovery under a previous HRC grant (HRC 01/276) of PR-104. This dinitrobenzamide mustard prodrug is reduced to cytotoxic DNA crosslinking metabolites in hypoxic tumour cells, and under aerobic conditions by the E. coli nitroreductase nfsB. PR-104 entered a first-in-human clinical trial in NZ in 2006 through the University of Auckland start-up company Proacta Inc. Ongoing clinical research is now focused on relapsed acute myeloid leukaemia (AML), in large part as a result of findings from the current HRC programme.