To compare the interactions of two topoisomerase II inhibitors, etoposide and idarubicin, with irradiation. Two mathematical modeling systems were used to assess the interactions. Hamster lung fibroblast cells (V79) were exposed to etoposide or idarubicin for 24 hours before or immediately after irradiation. Postradiation treatment with etoposide or idarubicin resulted in radiosensitization, as demonstrated by a decrease in the mean inactivation dose. Exposure to either drug before irradiation resulted in no radiosensitization. The first mathematical modeling system used was isobologram analysis. This analysis revealed a synergistic interaction if etoposide exposure followed irradiation. The interaction from the combination of irradiation and preradiation etoposide was within the envelope of additivity. Irradiation and postradiation idarubicin exposure also resulted in an interaction within the envelope of additivity, whereas preradiation idarubicin exposure resulted in a slightly less than additive interaction. Next, analyses were performed by the median effect principle. Synergistic interactions were demonstrated for combinations of etoposide and irradiation as well as idarubicin and irradiation. Synergistic interactions were more likely when drug exposure (either idarubicin or etoposide) followed irradiation. Experiments at various ratios of radiation dose to drug concentration showed that the likelihood of a synergistic interaction increased as the drug concentration increased relative to the radiation dose. The interaction of irradiation with topoisomerase II-reactive agents should be further explored in human tumor cell lines. © 1995, Mayo Foundation for Medical Education and Research. All rights reserved.