Cytocidal effects of misonidazole, Ro 03-8799, and RSU-1164 on euoxic and hypoxic BP-8 murine sarcoma cells at normal and elevated temperatures.

Euoxic and hypoxic BP-8 murine sarcoma cells were exposed for up to 3 hours to various concentrations of three nitroimidazole derivatives (misonidazole, Ro 03-8799, RSU-1164) at normal or elevated incubation temperatures. Cell survival was monitored with the iodine 125 (125I)-iododeoxyuridine prelabeling assay. When cell lethality 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 did not change the euoxic/hypoxic toxicity ratio for misonidazole and Ro 03-8799, but with RSU-1164 the toxicity ratio was increased significantly from 16 (1 hour) to 73 (3 hours). This increase was attributed to the bifunctional action of RSU-1164 as a combined electron-affinic and alkylating agent, with the alkylation component of cell killing becoming more pronounced after prolonged drug incubation under hypoxic conditions. 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. In short, based on cellular toxicity data, Ro 03-8799 appears to offer no advantage over misonidazole as a selective cytocidal agent for hypoxic cells, but RSU-1164 does provide a moderate therapeutic advantage.