Grégoire V, Ruifrok A C, Price R E, Brock W A, Hittelman W N, Plunkett W K, Ang K K
Department of Clinical Investigation, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
Radiother Oncol. 1995 Jul;36(1):50-5. doi: 10.1016/0167-8140(95)01563-v.
The effect of fludarabine (9-beta-D-arabinosyl-2-fluoroadenine-5'- monophosphate), an adenine nucleoside analogue, on the tolerance of the spinal cord to fractionated irradiation was studied in a rat model. Anesthetized female Fisher 344 rats received irradiation to 2 cm of the cervical spine with a telecobalt unit (dose rate 1.14 Gy/min). Radiation was administered in two, four or eight fractions spread over a 48-h period with or without fludarabine. Animals assigned to combined therapy received two daily intraperitoneal injections of fludarabine (150 mg/kg) given 3 h prior to the first daily radiation fraction. It was found that fludarabine reduced the iso-effect dose required to induce leg paresis at 9 months after irradiation for all fractionation schedules. Dose modification factors of 1.23, 1.29 and greater than 1.27 were obtained for two, four and eight fractions, respectively. Fitting the data with the direct analysis method of Thames et al. with an incomplete repair model [18] showed that the potentiating effect of fludarabine may be mediated through reduction in the number of 'tissue-rescuing units' (InK). Alpha and beta values were slightly but not significantly decreased, whereas the alpha/beta ratio was unchanged. These features suggest that fludarabine did not significantly inhibit cellular repair processes but rather reduced the spinal cord tolerance by a fixed additive toxic effect on the same target cells. In rodent models, the combination of fludarabine and fractionated radiation has previously been found to yield a therapeutic gain, i.e., the drug enhanced tumor response to a greater extent than it reduced normal tissue tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
在大鼠模型中研究了腺嘌呤核苷类似物氟达拉滨（9-β-D-阿拉伯糖基-2-氟腺嘌呤-5'-单磷酸）对脊髓分次照射耐受性的影响。麻醉的雌性Fisher 344大鼠用远距钴治疗机对颈椎2厘米处进行照射（剂量率1.14 Gy/分钟）。在48小时内分两次、四次或八次进行照射，同时或不同时给予氟达拉滨。接受联合治疗的动物在每日第一次照射前3小时腹腔注射两次氟达拉滨（150毫克/千克）。结果发现，对于所有分次照射方案，氟达拉滨均降低了照射后9个月诱导腿部麻痹所需的等效剂量。两次、四次和八次照射的剂量修正因子分别为1.23、1.29和大于1.27。用Thames等人的直接分析法和不完全修复模型拟合数据[18]表明，氟达拉滨的增效作用可能是通过减少“组织挽救单位”（InK）的数量介导的。α和β值略有下降但不显著，而α/β比值不变。这些特征表明，氟达拉滨并未显著抑制细胞修复过程，而是通过对相同靶细胞产生固定的附加毒性作用降低了脊髓耐受性。在啮齿动物模型中，先前已发现氟达拉滨与分次放疗联合使用可产生治疗增益，即该药物增强肿瘤反应的程度大于降低正常组织耐受性的程度。（摘要截短为250字）
