The Nitroreductase/CB1954 Enzyme-Prodrug System

The prodrug CB1954 (5-[aziridin-1-yl]-2,4-dinitrobenzamide) is a weak monofunctional alkylating agent originally synthesized at the Chester Beatty Laboratories in the late 1960s (1 ). The antitumor activity of CB1954 was determined by screening a panel of aziridines for cytotoxicity against the rat Walker 256 carcinoma. It is highly selective and effective against Walker tumor cells in vivo and in vitro with a therapeutic index of 70 (2 ). Based on the efficacy against the Walker carcinoma, a small clinical trial using CB1954 was initiated at the Royal Marsden Hospital in 1970. The results of this study are unpublished; however, a dose-limiting toxicity was reached (the major side effect being diarrhea) without any evidence of tumor regression (Wiltshaw, unpublished data). Recently, a clinical trial to determine the maximum tolerated dose (MTD) of CB1954 by intravenous and intraperitoneal routes has been performed in Birmingham. This study concluded that the MTD for CB1954 is 24 mg/m² by iv administration and 37.5 mg/m² by the ip route. Toxicity included diarrhea and elevation of liver transaminases (3 ).