OncoGel 瘤内给药后实验性脊髓内神经胶质瘤肉瘤大鼠出现瘫痪延迟发作。
Delayed onset of paresis in rats with experimental intramedullary spinal cord gliosarcoma following intratumoral administration of the paclitaxel delivery system OncoGel.
机构信息
Departments of Neurosurgery, The Johns HopkinsUniversity School of Medicine, Baltimore, Maryland, USA.
出版信息
J Neurosurg Spine. 2012 Jan;16(1):93-101. doi: 10.3171/2011.9.SPINE11435.
OBJECT
Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma.
METHODS
Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 μl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 μl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis.
RESULTS
OncoGel was safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml of paclitaxel; a dose of 5 μl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0, and no differences in median survival or BBB scores after treatment on Day 5.
CONCLUSIONS
OncoGel is safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml, prolongs median survival, and increases functional motor scores in rats challenged with an intramedullary gliosarcoma at the doses tested. This study suggests that locally delivered chemotherapeutic agents could be of temporary benefit in the treatment of malignant IMSCTs under experimental settings.
目的
治疗脊髓髓内的间变性或恶性肿瘤（IMSCT）的选择仍然有限。紫杉醇对实验性颅内神经胶质瘤具有很强的细胞毒性，对 IMSCT 的治疗可能有益，但中枢神经系统（CNS）穿透性差和毒性大限制了其应用。局部肿瘤内递送可以克服这些局限性。紫杉醇已被纳入可生物降解的凝胶库递送系统（OncoGel），本研究中作者评估了 OncoGel 椎管内注射在大鼠中的安全性及其对脊髓内大鼠神经胶质瘤肉瘤的疗效。
方法
使用 1.5 和 6.0mg/ml（5μl）浓度的 OncoGel 在 12 只 Fischer-344 大鼠中测试了椎管内 OncoGel 的安全性；并将中位生存期和功能运动评分（Basso-Beattie-Bresnahan[BBB]量表）与安慰剂（ReGel）和仅用培养基的注射组进行比较。将 61 只 Fischer-344 大鼠植入含有 10 万个细胞的脊髓内 9L 神经胶质瘤肉瘤，用 5μl 培养基进行注射，随机接受 OncoGel 治疗，32 只大鼠于肿瘤植入当天（OncoGel 剂量为 1.5mg/ml 或 3.0mg/ml），29 只大鼠于 5 天后（OncoGel 剂量为 1.5mg/ml 或 3.0mg/ml）进行注射。将中位生存期和 BBB 评分与 ReGel 治疗组和肿瘤仅植入组进行比较。动物在出现缺陷后死亡，进行组织病理学分析。
结果
在大鼠中，5μl 3.0mg/ml 的紫杉醇剂量下的 OncoGel 椎管内注射是安全的；5μl 6.0mg/ml 的剂量会导致 BBB 评分迅速恶化。OncoGel 浓度为 1.5mg/ml 和 3.0mg/ml 的紫杉醇，无论在第 0 天还是第 5 天给药，均能延长中位生存期并保持 BBB 评分，与对照组相比有显著改善。OncoGel 在第 0 天给予 1.5mg/ml 紫杉醇时，有 62.5%的大鼠长期存活。1.5mg/ml 与 3.0mg/ml 剂量的比较显示，在第 0 天给予 1.5mg/ml 紫杉醇的中位生存期更高，而第 5 天治疗后的中位生存期或 BBB 评分无差异。
结论
在大鼠中，5μl 3.0mg/ml 的 OncoGel 椎管内注射是安全的，可延长中位生存期，并提高脊髓内神经胶质瘤肉瘤大鼠的功能运动评分。该研究表明，在实验环境下，局部递药的化疗药物可能对恶性 IMSCT 的治疗有暂时的益处。
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