Expression of the bacterial nitroreductase enzyme in mammalian cells renders them selectively sensitive to killing by the prodrug CB1954

Expression of Escherichia coli B nitroreductase in established human tumor xenografts in mice results in potent antitumoral and bystander effects upon systemic administration of the prodrug CB1954

“…The prodrug CB1954, which is similarly inert, 19 has been shown to mediate potent in vitro tumor cell killing of cells engineered to express E. coli NTR as well as cocultured nonexpressing tumor cells. 11,20 In this study, we investigated the in vivo efficacy of the ntr/CB1954 system using xenograft models of hepatocellular carcinoma and squamous carcinoma of the head and neck. These tumor types were selected because they will be two of the earliest clinical targets for the system, as they are amenable to targeting ntr gene delivery by direct i.t.…”

“…Cellular thioesters such as acetyl coenzyme A subsequently convert the latter into a powerful bifunctional alkylating agent 10 that can kill both proliferating and nonproliferating cells. 11,12 At the molecular level, this cell killing involves induction of interstrand DNA cross-links and apoptosis. 10,12,13 Tumor cell lines expressing NTR in vitro after stable transfection with the ntr gene are usually at least a hundred times more sensitive to CB1954 than untransfected cells.…”

Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil

“…Interestingly, studies of other enzyme -prodrug combinations also suggest a 'distant bystander effect' thought to be a systemic immunemediated response to local tumour cell killing (Link et al, 1997). Other potential advantages of the NR/CB1954 combination are the ability to kill cells in a cell cycle-independent manner and the lack of cross-resistance with other commonly used cytotoxic agents (Bridgewater et al, 1995;Knox, 1998). A recent phase I clinical trial has confirmed that CB1954 is a well-tolerated prodrug that can be administered intravenously or intraperitoneally at doses sufficient for a VDEPT approach to be feasible in the treatment of ovarian cancer (Chung-Faye et al, 2001).…”

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

“…Escherochia coli nitroimidazole reductase (nitroreductase, NTR) can bioactivate CB1954 much more efficiently than even rat DTdiaphorase (Knox et al, 1992) and human tumour cells transduced with retroviral vectors to express this enzyme are very sensitive to the drug (Bridgewater et al, 1995;Bailey et al, 1996;Green et al, 1997;McNeish et al, 1998). It was shown that NTR-expressing cell lines are 500 -2000-fold more sensitive to CB1954 than parental cell lines (Green et al, 1997;McNeish et al, 1998).…”