Sensitisation of human ovarian cancer cells to killing by the prodrug CB1954 following retroviral or adenoviral transfer of the E. coli nitroreductase gene.

Abstract

The enzyme nitroreductase from E. coli can reduce the relatively non-toxic prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) to the 2- or 4-hydroxylamino derivatives; the latter is a potent cytotoxic agent, which following further non-enzymatic reaction with thioesters, leads to the generation of interstrand crosslinks in DNA [1–4] (Figure 1a). These cannot be efficiently repaired by the cell, and lead to cell death. Nitroreductase and CB1954 are therefore of interest as an enzyme-prodrug combination for “virus directed enzyme-prodrug therapy” (VDEPT) of cancer [5, 6]. We describe here the use of retroviral and adenoviral vectors to deliver the gene to human ovarian cancer cells in vitro, and their consequent sensitisation to CB1954.