Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats.
Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats.
复制标题
雷帕霉素的局部递送：大鼠实验性恶性神经胶质瘤模型的毒性和功效研究。
DOI：
10.1093/neuonc/nor050
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发表时间：
2011
期刊：
影响因子：
15.9
通讯作者：
Brem,Henry
中科院分区：
文献类型：
--
作者：
Tyler,Betty;Wadsworth,Scott;Recinos,Violette;Mehta,Vivek;Vellimana,Ananth;Li,Khan;Rosenblatt,Joel;Do,Hiep;Gallia,GaryL;Siu,I-Mei;Wicks,RobertT;Rudek,MichelleA;Zhao,Ming;Brem,Henry
雷帕霉素是一种抗增殖剂，可有效治疗肾细胞癌和复发性乳腺癌。我们提出，雷帕霉素抑制剂的这种有效的哺乳动物靶点也可能用于治疗神经胶质瘤。我们检查了雷帕霉素对啮齿动物神经胶质瘤细胞系的细胞毒性，确定了雷帕霉素颅内递送时的毒性，并研究了雷帕霉素局部递送在体内治疗实验性恶性神经胶质瘤的功效。我们还检查了雷帕霉素的剂量依赖性疗效以及局部递送雷帕霉素与放射治疗相结合时的效果。雷帕霉素对 9L 细胞具有细胞毒性，浓度为 0.01 µg/mL 时可抑制 34% 的生长。当雷帕霉素以 0.3%、3% 和 30% 的负荷剂量掺入可生物降解的己内酯-乙交酯 (35:65) 聚合物珠并植入颅内时，未观察到体内毒性。进行了三项单独的功效研究，以测试雷帕霉素珠效果的再现性以及该治疗方法的有效性。使用最高剂量雷帕霉素珠（30%）治疗的动物始终表现出比对照组和安慰剂组显着更长的存活时间。与对照组相比，所有剂量递增的雷帕霉素珠治疗组（0.3%、3%和30%）在与肿瘤同时治疗以及肿瘤放置后延迟治疗的情况下，存活率均显着增加。放射治疗加上 30% 雷帕霉素珠的同时治疗比单独治疗中的任何一种治疗都显着延长了生存期。这些结果表明，应进一步研究雷帕霉素局部给药治疗神经胶质瘤的效果。
Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated.