In vitro hypoxic cytotoxicity of nitroimidazoles: Uptake and cell cycle phase specificity

Abstract

The hypoxic cytotoxicity of four different 2-nitroimidazoles of similar electron affinities but different lipophilicities was compared using EMT6/Ro mouse mammary tumor cells in exponential growth phase in severely (<20 ppm) hypoxic conditions. The relative cytotoxicities were misonidazole (MISO) = desmethylmisonidazole (9963) > SR-2508 ⪢ SR-2555 indicating that the compounds with the lowest lipophilicity were less cytotoxic. The rates of uptake of these compounds were MISO > 9963 > SR-2508 = SR-2555. These data together with comparisons of the amounts of cell-associated compounds indicate that the similarity in toxicity of MISO and 9963 can be related to a general similarity in their pharmacokinetics, but that other unknown factors must be considered to explain the relative toxicity of SR-2508 and SR-2555. In other experiments, EMT6/Ro cells synchronized using centrifugal elutriation were most sensitive in hypoxia to MISO at the late G 1-early S phase of the cell cycle. These data indicate the importance of considering cellular and subcellular distribution of these nitroimidazoles as well as possible cell cycle specificity for cytotoxicity in interpreting relative effectiveness of different compounds in responses of mixed populations of cells in cultures or tumors.