Addition of misonidazole, etanidazole, or hyperthermia to treatment with fluosol-DA/carbogen/radiation.

The antitumor efficacy of adding the nitroimidazole radiosensitizing drugs misonidazole and etanidazole or hyperthermia (43 degrees C for 30 min) to Fluosol-DA/carbogen (95% O2/5% CO2) and irradiation was tested in the FSaIIC tumor system. Both the nitroimidazole drugs and hyperthermia produced additional tumor growth delays and tumor cell cytotoxicity when given with Fluosol-DA/carbogen, either before or after irradiation. For each of the modalities tested, the dose-modifying effect was greater when that therapy preceded rather than followed irradiation (misonidazole 2.7 vs. 1.9, etanidazole 2.4 vs. 1.7, hyperthermia 4.0 vs. 1.7 relative to the effect of radiotherapy alone). Because the nitroimidazole drugs must be present before radiation is administered to exert their radiosensitizing effect, the increase in tumor growth delay observed when these drugs cytotoxic to hypoxic cells were administered following Fluosol-DA/carbogen and irradiation suggests that Fluosol-DA/carbogen could not fully oxygenate the tumors and that the nitroimidazole drugs were effectively toxic to residual hypoxic cells. The treatment Fluosol-DA/carbogen----hyperthermia----irradiation produced a marked increase in tumor growth delay not seen with the sequence Fluosol-DA/carbogen----irradiation----hyperthermia. The results indicate that a treatment combination of radiation sensitizers may be more effective than irradiation plus Fluosol-DA with oxygen breathing alone.