Grégoire V, Hunter N, Brock W A, Milas L, Plunkett W, Hittelman W N
Department of Clinical Investigation, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Int J Radiat Oncol Biol Phys. 1994 Sep 30;30(2):363-71. doi: 10.1016/0360-3016(94)90016-7.
Fludarabine, an adenine nucleoside analogue, and an effective inhibitor of chromosome repair, was previously shown to synergistically enhance radiation-induced regrowth delay in three murine tumors. The purpose of this study was to assess whether fludarabine can increase the therapeutic ratio of radiotherapy in murine tumors, that is, to increase local tumor control without significantly modifying the radiation-induced normal tissue response.
Mice bearing 8-mm tumors in the right thigh (SA-NH sarcoma and MCA-K mammary carcinoma) were given 800 mg/kg fludarabine IP 3 h or 24 h before single doses of photon irradiation. Local tumor control was assessed by the TCD50 assay 100 days after treatment. Acute normal tissue toxicity was assessed in the skin (degree of epilation 30 days after irradiation) and in the jejunum (crypt regeneration assay), and late normal tissue toxicity was assessed by a leg contracture assay 120 days after treatment.
In both tumors and with both drug schedules, fludarabine enhanced radiation-induced local tumor control (dose modification factors (DMF) of 1.24 (95% confidence limits 1.19-1.31) and 1.26 (95% confidence limits 1.20-1.32) for SA-NH, and 1.38 (95% confidence limits 1.25-1.50) and 1.35 (95% confidence limits 1.22-1.16) for MCA-K tumors). When given 3 h before radiation, fludarabine offered a slight protection from skin toxicity (DMF = 0.83, 95% confidence limits 0.77-0.86) but enhanced jejunum toxicity (DMF = 1.53). When fludarabine was given 24 h before irradiation, the reverse trend was observed (DMF = 1.11 (95% confidence limits 1.07-1.16) and 0.89, respectively). No enhancement of leg contracture was observed for either fludarabine schedule.
The data presented here demonstrate that fludarabine can potentiate local tumor control induced by single-dose irradiation. While jejunum sensitization limited the relative effectiveness when fludarabine was administered 3 h before irradiation, a therapeutic ratio greater than one was always achieved when fludarabine was given 24 h before irradiation.
氟达拉滨是一种腺嘌呤核苷类似物，也是一种有效的染色体修复抑制剂，先前已证明它能协同增强三种小鼠肿瘤的辐射诱导再生长延迟。本研究的目的是评估氟达拉滨是否能提高小鼠肿瘤放疗的治疗增益比，即提高局部肿瘤控制率，同时不显著改变辐射诱导的正常组织反应。
右大腿长有8毫米肿瘤（SA-NH肉瘤和MCA-K乳腺癌）的小鼠，在单次光子照射前3小时或24小时腹腔注射800毫克/千克氟达拉滨。治疗100天后通过TCD50测定评估局部肿瘤控制情况。在皮肤（照射后30天的脱毛程度）和空肠（隐窝再生测定）评估急性正常组织毒性，在治疗120天后通过腿部挛缩测定评估晚期正常组织毒性。
在两种肿瘤以及两种给药方案中，氟达拉滨均增强了辐射诱导的局部肿瘤控制（SA-NH的剂量修正因子（DMF）分别为1.24（95%置信区间1.19 - 1.31）和1.26（95%置信区间1.20 - 1.32），MCA-K肿瘤的DMF分别为1.38（95%置信区间1.25 - 1.50）和1.35（95%置信区间1.22 - 1.16））。在辐射前3小时给药时，氟达拉滨对皮肤毒性有轻微保护作用（DMF = 0.83，95%置信区间0.77 - 0.86），但增强了空肠毒性（DMF = 1.53）。当氟达拉滨在照射前24小时给药时，观察到相反的趋势（DMF分别为1.11（95%置信区间1.07 - 1.16）和0.89）。两种氟达拉滨给药方案均未观察到腿部挛缩增强。
此处给出的数据表明氟达拉滨可增强单剂量照射诱导的局部肿瘤控制。当氟达拉滨在照射前3小时给药时空肠致敏限制了相对有效性，但当氟达拉滨在照射前24小时给药时，总能实现大于1的治疗增益比。
