Enhanced tumor responses through therapies combining CCNU, MISO and radiation

Studies were performed to determine whether the radiation sensitizer misonidazole (MISO) could enhance the tumor control probability in a treatment strategy combining radiation and the nitrosourea 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). In initial experiments KHT sarcoma-bearing mice were injected with 1.0 mg/g of MISO simultaneously with a 20 mg/kg dose of CCNU 30-40 min prior to irradiation (1500 rad). These timings were chosen to maximize the effectiveness of MISO both as a chemopotentiator and radiosensitizer. With this treatment protocol approximately 60% of the mice were found to be tumor-free 100 days post treatment. By comparison all 2 agent combinations led to 0% cures. To evaluate the relative importance of chemopotentiation versus radiosensitization in the 3 agent protocol, tumors were treated with MISO plus one anti-tumor agent (either radiation of CCNU) and then at times ranging from 0 to 24 hr later exposed to the other agent. When the time between treatments was 0 to 6 hr, a 60 to 80% tumor control rate was achieved for both MISO plus radiation followed by CCNU and MISO plus CCNU followed by radiation. However if the time interval was increased to 18 or 24 hr, the cure rate in the former treatment regimen dropped to 10% while that of the latter remained high at 40%. These results were not due to the radiation-CCNU sequence but rather reflected the ability of the sensitizer to act as a chemopotentiator when CCNU is given 0 to 6 hr after the MISO-radiation combination. This was not the case when the MISO-radiation combination was administered 18 or 24 hr prior to CCNU. The data therefore indicate that 1) improved tumor responses may be achieved when MISO is added to a radiation-chemotherapy combination and 2) MISO may be more effective in such a protocol when utilized as a chemopotentiator.