The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells
The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells
复制标题
DOI：
10.1093/neuonc/nor069
复制
发表时间：
2011-09-01
期刊：
影响因子：
15.9
通讯作者：
Pruschy, Martin
中科院分区：
文献类型：
--
作者：
Oehler, Christoph;von Bueren, Andre O.;Pruschy, Martin
髓母细胞瘤的同步放化疗包括微管破坏剂长春新碱;然而，长春新碱单独或作为联合治疗方案的一部分具有高度毒性。因此，一个主要的目标是用新的有效的化疗药物取代长春新碱，特别是用微管稳定和去稳定的化合物，具有更大的治疗窗口。在这里，我们研究了帕土匹隆（埃博霉素B [EPO 906]），一种新型的，非紫杉烷相关的和非神经毒性的微管稳定剂在人髓母细胞瘤细胞系的抗增殖，细胞毒性和放射增敏作用。在3种代表性的人髓母细胞瘤细胞系D341 Med、D425 Med和DAOY中测定帕妥匹隆单独和与电离辐射组合的抗增殖和细胞毒性作用。帕土匹隆单独有效地降低了在皮摩尔浓度（50-200 pM）下测试的所有髓母细胞瘤细胞系的增殖活性和克隆形成，并且与临床相关剂量的电离辐射（2或5戈伊）组合导致至少累加的抗克隆形成作用。细胞周期分析显示，暴露于帕妥匹隆后，以剂量和治疗依赖性方式连续G2-M期阻滞和亚G1期蓄积。在源自D425 Med细胞的肿瘤异种移植物中，帕土匹隆和分次照射（1 x 2 mg/kg加3 x 3戈伊）的最小治疗方案导致2种单一治疗方式单独延长肿瘤生长延迟，联合治疗方式产生超累加治疗反应，肿瘤完全消退。这些结果证明了帕土匹隆对髓母细胞瘤细胞系的有效性，并表明帕土匹隆是替代长春新碱作为电离辐射联合治疗策略的一部分的有希望的候选药物。
Concurrent radiochemotherapy for medulloblastoma includes the microtubule disrupting agent vincristine; however, vincristine alone or as part of a combined treatment regimen is highly toxic. A major goal is therefore to replace vincristine with novel potent chemotherapeutic agents-in particular, with microtubule stabilizing and destabilizing compounds-with a larger therapeutic window. Here, we investigated the antiproliferative, cytotoxic and radiosensitizing effect of patupilone (epothilone B [EPO906]), a novel, non-taxane-related and nonneurotoxic microtubule-stabilizing agent in human medulloblastoma cell lines. The antiproliferative and cytotoxic effects of patupilone alone and in combination with ionizing radiation was determined in the 3 representative human medulloblastoma cell lines D341Med, D425Med, and DAOY. Patupilone alone effectively reduced the proliferative activity and clonogenicity of all medulloblastoma cell lines tested at picomolar concentrations (50-200 pM) and resulted in an at least additive anticlonogenic effect in combination with clinically relevant doses of ionizing radiation (2 or 5 Gy). Cell-cycle analysis revealed a sequential G2-M arrest and sub-G1 accumulation in a dose-and treatment-dependent manner after exposure to patupilone. In tumor xenografts derived from D425Med cells, a minimal treatment regimen with patupilone and fractionated irradiation (1 x 2 mg/kg plus 3 x 3 Gy) resulted in an extended tumor growth delay for the 2 single treatment modalities alone and a supra-additive treatment response for the combined treatment modality, with complete tumor regressions. These results demonstrate the potent efficacy of patupilone against medulloblastoma cell lines and indicate that patupilone represents a promising candidate to replace vincristine as part of a combined treatment strategy with ionizing radiation.