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

Abstract

Fludarabine, an effective repair inhibitor of radiation-induced chromosome breaks, and indomethacin, an inhibitor of prostaglandin synthesis, were shown previously to improve the therapeutic ratio of radiotherapy for murine tumors. The purpose of this study was to determine whether the combination of these two radiosensitizers with different mechanisms of action could further increase the therapeutic ratio of radiotherapy in an FSA mouse sarcoma after single and fractionated irradiation. The effect of the combined treatment on tumors was assessed by the local tumor control assay (TCD50) in mice bearing an FSA sarcoma in the leg. The effect of the combination on normal tissues was assessed by skin desquamation, hair loss and leg contracture in the legs of non-tumor-bearing mice. For the TCD50 assay, after single irradiation, the radiation dose modification factor (DMF) reached 1.2 for both indomethacin (35 micrograms/ml in the drinking water for 10 days) and fludarabine (800 mg/kg intraperitoneally 3 h prior to irradiation). For both drugs combined, the DMF increased to 1.7. No significant increase in normal tissue toxicity was observed with any of the combinations. After fractionated irradiation (16 fractions over 4 days), the DMFs for local tumor control reached 1.3 for indomethacin and 1.8 for fludarabine darabine (400 mg/kg every day for 4 days). The combination of both drugs produced a DMF of 2.0. None of the combinations altered the effects of radiation on skin desquamation, hair loss or leg contracture significantly. The present study suggests that the therapeutic ratio of radiotherapy for a murine sarcoma can be improved by the combination of indomethacin and fludarabine, two agents differing in their mechanisms of radiopotentiation.