Radiosensitization and Hypoxic Cell Toxicity of NLA‐1 and NLA‐2, Two New Bioreductive Compounds

Two new bioreductive compounds, 9‐[3‐(2‐nitro‐l‐imidazolyl)propylamino]acridine hydrochloride (NLA‐1) and 9‐[2‐(2‐nitro‐l‐imidazoryl)ethylamino]acridine hydrochloride (NLA‐2), have been prepared. They feature an acridine ring to intercalate with DNA, a 2‐nitroimidazole ring as the radiosensitizing moiety and an amino functionality for increased DNA‐binding and hydrophilicity. Time and concentration dependent cytotoxicity as well as radiosensitization efficacy of the two compounds under hypoxic or aerobic conditions were determined in vitro using V‐79 cells and an MTT colorimetric or clonogenic assay. The isosensitization point (ISP), defined as that drug concentration which results in the same survival decrement upon exposure of hypoxic or oxygenated cells to a given radiation dose, has been determined for both compounds at 7.5 Gy and the values are significantly lower than the ISPs of 5‐[3‐(2‐nitro‐l‐imidazolyl)propyl]phenanthridinium bromide, 2‐(2‐nitro‐l‐imidazolyl)ethylamine or misonidazole (MISO). NLA‐1 and NLA‐2 are potent hypoxic cytotoxins and on a concentration basis, more potent than MISO as radiosensitizers in vitro. The sensitization enhancement ratios were significantly increased when 1 h drug preincubation under hypoxia at 37°C was applied, before irradiation at room temperature.