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.