The Bystander Effect of the Nitroreductase/CB 1954 Enzyme/Prodrug System Is Due to a Cell-Permeable Metabolite

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Abstract
The bystander effect is an important part of tumor kill using gene-directed enzyme prodrug therapy (GDEPT). Recently, we have described a novel enzyme prodrug system using bacterial nitroreductase and the prodrug CB1954 (NTR/CB1954). We demonstrate here the presence of a cell-permeable cytotoxic activity in the conditioned growth medium of nitroreductase (NTR)-transduced cells treated with CB1954 and show that its appearance corresponds to the appearance of two metabolites of CB1954 previously identified (Friedlos et al., 1992). The degree of bystander effect and the degree of transferred cytotoxicity correlates with the level of NTR enzyme expression. Two other prodrugs for NTR show little bystander killing and do not produce detectable cell permeable metabolites. The elucidation of the mechanism of the bystander effect may allow the more effective use of NTR/CB1954. GDEPT is a tumor therapy strategy that exploits the ability of a foreign enzyme to convert a prodrug into a toxic metabolite. Current gene delivery mechanisms cannot transduce all cells within a tumor, making the ability to kill not only transduced cells but adjacent untransduced cells an important part of an enzyme/prodrug system. We describe the mechanism of this bystander effect for the nitroreductase/CB1954 system and suggest how this might provide improved killing in a some tumor microenvironments.

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