Improvement in therapeutic ratio of radiotherapy for a murine sarcoma by indomethacin plus misonidazole

Abstract

In this study we asked whether the improvement in the therapeutic ratio of radiotherapy by indomethacin (INDO), which potentiates tumor radioresponse through stimulation of the immune system, could be further improved by combining it with the hypoxic cell radiosensitizer misonidazole (MISO). Mice bearing the syngeneic sarcoma fibrosarcoma (8 mm) in the leg were treated with single graded doses of gamma-rays to the tumor or with irradiation combined with INDO, MISO, or both drugs. Local tumor control was the end point of tumor radioresponse. In addition, the effect of these drugs on radiation-caused hair loss and leg contractures was assessed. INDO increased tumor radioresponse by a factor of 1.31, but it did not affect either hair loss or leg contractures. MISO increased tumor radioresponse by a factor of 1.86, hair loss by a factor of 1.69, and leg contractures by a factor of 1.54, thus providing only a small therapeutic gain. The combined INDO plus MISO treatment increased tumor radioresponse by a factor of 2.72, which was more than the additive effect of the individual drugs. On the other hand, the combined treatment caused no additional hair loss compared to that caused by MISO only. Overall, our results show that INDO plus MISO treatment increased tumor radioresponse more than INDO or MISO alone and provided a significant therapeutic gain. Furthermore, they illustrate that combinations of two radiopotentiating agents with different mechanisms of action may improve the radiotherapeutic effect.