Grégoire V, Hunter N R, Brock W A, Hittelman W N, Plunkett W, Milas L
Department of Clinical Investigations, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Radiat Res. 1996 Nov;146(5):548-53.
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.
氟达拉滨是一种有效的辐射诱导染色体断裂修复抑制剂，吲哚美辛是一种前列腺素合成抑制剂，先前已证明它们可提高小鼠肿瘤放疗的治疗增益比。本研究的目的是确定这两种作用机制不同的放射增敏剂联合使用是否能在单次和分次照射后进一步提高FSA小鼠肉瘤放疗的治疗增益比。通过对腿部患有FSA肉瘤的小鼠进行局部肿瘤控制试验（TCD50）来评估联合治疗对肿瘤的影响。通过对无肿瘤小鼠腿部的皮肤脱屑、脱发和腿部挛缩来评估联合治疗对正常组织的影响。对于TCD50试验，单次照射后，吲哚美辛（饮用水中35微克/毫升，持续10天）和氟达拉滨（照射前3小时腹腔注射800毫克/千克）的辐射剂量修正因子（DMF）均达到1.2。两种药物联合使用时，DMF增加到1.7。任何联合用药均未观察到正常组织毒性显著增加。分次照射（4天内照射16次）后，吲哚美辛的局部肿瘤控制DMF达到1.3，氟达拉滨（每天400毫克/千克，持续4天）的DMF达到1.8。两种药物联合使用产生的DMF为2.0。任何联合用药均未显著改变辐射对皮肤脱屑、脱发或腿部挛缩的影响。本研究表明，吲哚美辛和氟达拉滨联合使用可提高小鼠肉瘤放疗的治疗增益比，这两种药物的放射增敏机制不同。
