Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres.
Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres.
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DOI：
10.3171/2014.1.jns13235
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发表时间：
2014-05
影响因子：
4.1
通讯作者：
Walter KA
中科院分区：
文献类型：
--
作者：
Gabikian P;Tyler BM;Zhang I;Li KW;Brem H;Walter KA
本研究的目的是证明紫杉醇可以作为恶性胶质瘤的放射增敏剂在体内和体外发挥作用。采用人U373MG和大鼠9L胶质瘤细胞系体外实验，研究紫杉醇的放射增敏作用。细胞周期阻滞反应紫杉醇暴露定量流式细胞术。细胞随后被照射，并使用克隆测定法测量毒性。在Fischer 344大鼠中植入颅内9L胶质瘤进行了体内研究。大鼠分别接受对照聚合物植入、紫杉醇控释聚合物、放疗或两者联合治疗。研究的终点是生存。流式细胞术显示，在紫杉醇暴露6-12小时后，U373MG和9L细胞中G2-M均停止。给予联合治疗的顺序是显著的。紫杉醇治疗后6-12小时的放射治疗（XRT）导致菌落形成的协同减少。这种影响大于单独治疗的影响，也大于辐射暴露后紫杉醇的影响。与任何其他治疗（包括放疗后紫杉醇治疗）相比，接受紫杉醇聚合物治疗的9L胶质瘤肿瘤大鼠在生存方面表现出协同改善。对照动物的中位生存期为13天；单用紫杉醇治疗21天；单独接受XRT治疗的患者为21天；接受XRT治疗后再接受紫杉醇治疗的患者，45天；紫杉醇治疗后XRT治疗超过150天（p < 0.0001）。这些结果表明，紫杉醇是一种有效的恶性胶质瘤放射增敏剂，因为它通过引起G2-M阻滞使胶质瘤细胞对电离辐射更敏感，并诱导对放化疗的协同反应。
The aim of this study was to demonstrate that paclitaxel could function as a radiosensitizer for malignant glioma in vitro and in vivo. The radiosensitizing effect of paclitaxel was tested in vitro using the human U373MG and rat 9L glioma cell lines. Cell cycle arrest in response to paclitaxel exposure was quantified by flow cytometry. Cells were subsequently irradiated, and toxicity was measured using the clonogenic assay. In vivo studies were performed in Fischer 344 rats implanted with intracranial 9L gliosarcoma. Rats were treated with control polymer implants, paclitaxel controlled-release polymers, radiotherapy, or a combination of the 2 treatments. The study end point was survival. Flow cytometry demonstrated G2-M arrest in both U373MG and 9L cells following 6–12 hours of paclitaxel exposure. The order in which the combination treatment was administered was significant. Exposure to radiation treatment (XRT) during the 6–12 hours after paclitaxel treatment resulted in a synergistic reduction in colony formation. This effect was greater than the effect from either treatment alone and was also greater than the effect of radiation exposure followed by paclitaxel. Rats bearing 9L gliosarcoma tumors treated with paclitaxel polymer administration followed by single-fraction radiotherapy demonstrated a synergistic improvement in survival compared with any other treatment, including radiotherapy followed by paclitaxel treatment. Median survival for control animals was 13 days; for those treated with paclitaxel alone, 21 days; for those treated with XRT alone, 21 days; for those treated with XRT followed by paclitaxel, 45 days; and for those treated with paclitaxel followed by XRT, more than 150 days (p < 0.0001). These results indicate that paclitaxel is an effective radiosensitizer for malignant gliomas because it renders glioma cells more sensitive to ionizing radiation by causing G2-M arrest, and induces a synergistic response to chemoradiotherapy.