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.