Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
J Neurosurg. 2010 Aug;113(2):210-7. doi: 10.3171/2009.11.JNS08162.
Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma.
Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5.
Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy-only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point.
OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.
紫杉醇是一种细胞增殖抑制剂/放射增敏剂，尽管在体外对神经胶质瘤有效，但全身给药时穿透中枢神经系统的能力差，且具有剂量限制毒性。OncoGel（紫杉醇在 Re-Gel 中的制剂）在放置到中枢神经系统时提供了紫杉醇的局部控释。作者评估了颅内 9L 神经胶质瘤肉瘤大鼠中 OncoGel 的安全性和疗效。
安全性研究包括颅内给予递增体积的 ReGel 和含有 1.5 毫克/毫升（OncoGel 1.5）或 6.3 毫克/毫升（OncoGel 6.3）紫杉醇的 OncoGel。18 只 Fischer-344 大鼠进行了体内放射性标记的生物分布研究，以确定脑内分布。疗效研究比较了对照组、仅给予 ReGel、仅给予放射治疗、给予 OncoGel 6.3 或 OncoGel 6.3 联合放射治疗的总生存期。ReGel 和 OncoGel 6.3 分别在肿瘤植入（第 0 天）或 5 天后（第 5 天）同时给予。第 5 天给予放射治疗。
对照组和 ReGel 动物在 17 天内死于肿瘤。Onco-Gel 6.3 组第 0 天（中位 31 天；p = 0.0001）、第 5 天（中位 17 天；p = 0.02）和单独放射治疗组（中位 26 天；p = 0.0001）的生存时间显著延长与对照组相比。接受 OncoGel 和放射治疗的动物具有最长的中位生存期：第 0 天联合 OncoGel 6.3 和放射治疗组为 83 天，第 5 天联合 OncoGel 6.3 组为 32 天（与对照组相比，p = 0.0001）。120 天后，OncoGel 第 0 天组有 37.5%的动物、OncoGel 6.3 第 0 天联合放射治疗组有 37.5%的动物和 OncoGel 6.3 第 5 天联合放射治疗组有 12.5%的动物存活。在生物分布研究中，在 OncoGel 注射后 3 周内观察到同侧半球的放射性物质，在注射后 3 小时检测到最高放射性物质。对侧半球观察到的最高放射性剂量出现在第 3 天时间点。
含 6.3 毫克/毫升紫杉醇的 OncoGel 颅内注射安全，第 0 天给药有效。当与放射治疗联合使用时，联合治疗比单独治疗更有效，应在临床上研究用于治疗恶性神经胶质瘤。
