Eshleman Jeffrey S, Carlson Brett L, Mladek Ann C, Kastner Brian D, Shide Kathleen L, Sarkaria Jann N
Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Cancer Res. 2002 Dec 15;62(24):7291-7.
The mammalian target of rapamycin (mTOR) modulates key signaling pathways that promote uncontrolled proliferation of glioblastoma multiforme (GBM). Because rapid tumor proliferation may contribute to the clinical radioresistance of GBM tumors, the combination of rapamycin, a selective mTOR inhibitor, and radiation was studied in vitro and in vivo in a GBM model. In monolayer cultures of U87 and SKMG-3 cells, rapamycin had no impact on radiation sensitivity. In contrast, rapamycin significantly enhanced the efficacy of fractionated radiation of established U87 xenografts in nude mice. Similar effects were seen in U87 spheroids treated with rapamycin and radiation, which suggests that the sensitizing effects of this drug are dependent on disruption of mTOR signaling pathways specifically within tumor cells. Inhibition of these signaling pathways can lead to inhibition of G(1)-specific cyclin-dependent kinase activities, and this could contribute to the sensitizing effects of rapamycin. Consistent with this idea, roscovitine, a specific cyclin-dependent kinase inhibitor, also enhanced the efficacy of fractionated radiation in U87 spheroids. These data demonstrate that inhibition of tumor proliferation does not diminish the efficacy of fractionated radiation and suggest that disruption of key signal transduction pathways may significantly enhance the effectiveness of radiation therapy in malignant gliomas.
雷帕霉素的哺乳动物靶点（mTOR）调节着促进多形性胶质母细胞瘤（GBM）不受控制增殖的关键信号通路。由于肿瘤的快速增殖可能导致GBM肿瘤产生临床放射抗性，因此在体外和体内的GBM模型中研究了选择性mTOR抑制剂雷帕霉素与放疗的联合应用。在U87和SKMG-3细胞的单层培养中，雷帕霉素对放射敏感性没有影响。相反，雷帕霉素显著增强了已建立的U87裸鼠异种移植瘤分次放疗的疗效。在用雷帕霉素和放疗处理的U87球体中也观察到了类似的效果，这表明该药物的增敏作用取决于肿瘤细胞内mTOR信号通路的破坏。抑制这些信号通路可导致G1期特异性细胞周期蛋白依赖性激酶活性受到抑制，这可能是雷帕霉素产生增敏作用的原因。与此观点一致，特异性细胞周期蛋白依赖性激酶抑制剂罗可辛也增强了U87球体分次放疗的疗效。这些数据表明，抑制肿瘤增殖并不会降低分次放疗的疗效，并提示关键信号转导通路的破坏可能会显著提高恶性胶质瘤放射治疗的有效性。
