INVESTIGATION OF ALTERNATIVE PRODRUGS FOR USE WITH ESCHERICHIA-COLI NITROREDUCTASE IN SUICIDE GENE APPROACHES TO CANCER-THERAPY

The most commonly employed 'suicide' gene/prodrug system used in cance r gene therapy is the herpes simplex virus thymidine kinase (HSVtk)/ga nciclovir system. We have examined the efficacy of an alternative appr oach utilising the E. coli nitroreductase B enzyme with CB1954 and a v ariety of other prodrugs. V79 cells transfected with a nitroreductase expression vector were up to 770-fold more sensitive to CB1954 than co ntrol non-expressing cells. In general other prodrugs which were found by HPLC to act as substrates for purified E. coli nitroreductase also exhibited increased cytotoxicity against the nitroreductase-expressin g cells, although this correlation was not absolute. In particular nit rofurazone (97-fold) and additional aromatic nitro-compounds (nine- to 50-fold) showed a large differential whereas the quinones and the ant imetabolite, 5-FU, were less effective (<three-fold). The results supp ort the possibility of using nitroreductase and CB1954 for 'suicide ge ne' therapy and in addition suggest that alternative prodrugs, such as nitrofurazone, warrant further investigation in this novel approach.