Cytocidal and radiosensitizing properties of two newly developed nitroimidazole drugs: Ro 03-8799 ampersand RSU-1164

The cytocidal and radiosensitizing effects of two newly developed 2-nitroimidazole derivatives (Ro 03-8799 and RSU-1164) were evaluated with the original compound, misonidazole, serving as a reference agent. More specifically, euoxic and hypoxic BP-8 murine sarcoma cells were exposed for up to 3 hours to various concentrations of the three nitroimidazole derivatives, with or without irradiation, and the resulting cell lethality was monitored with the 125IUdR prelabeling assay. When cell death was evaluated as a function of drug molarity, the three nitroimidazoles displayed widely different toxicities, but when expressed in terms of toxicity ratio between euoxic and hypoxic cells, all three drugs showed nearly identical toxicity differentials of 16 to 18 in 1 hour drug incubation experiments. Prolonging the treatment period to 3 hours with RSU-1164, the toxicity ratio was increased significantly from 16 to 73. This increase was attributed to the bifunctional action of RSU-1164 as a combined electron-affinic and alkylating agent, with the alkylation component of hypoxic cell killing becoming more pronounced after prolonged drug incubation. Combined administration of hyperthermia and nitroimidazoles increased drug-induced cell lethality for all three agents, but did not materially change the relative toxicity differential between euoxic and hypoxic cells