Panner Amith, Parsa Andrew T, Pieper Russell O
Brain Tumor Research Center, Department of Neurological Surgery and the Comprehensive Cancer Center, University of California, San Francisco, CA 94143-0875, USA.
Expert Rev Anticancer Ther. 2006 Sep;6(9):1313-22. doi: 10.1586/14737140.6.9.1313.
The mammalian target of rapamycin (mTOR) plays a critical role in the regulation of cell growth, proliferation and survival. Components of the mTOR pathway are activated in a variety of tumors, including glioblastoma multiforme (GBM), and we have found that one surprising consequence of mTOR pathway activation is resistance of GBMs to the proapoptotic effects of agents such as APO2L/TRAIL. mTOR inhibition has become feasible following the development of rapamycin and comparable analogs with improved pharmacological properties, including CCI-779, RAD001 and AP23573. Numerous studies have also demonstrated promising proapoptotic activity, with relatively mild side effects, using rapamycin analogs in vitro and in vivo in conjunction with APO2L/TRAIL. These studies suggest that mTOR inhibitors can be combined with APO2L/TRAIL as a potential tumor-selective therapy.
雷帕霉素的哺乳动物靶点（mTOR）在细胞生长、增殖和存活的调节中起着关键作用。mTOR信号通路的组成部分在包括多形性胶质母细胞瘤（GBM）在内的多种肿瘤中被激活，并且我们发现mTOR信号通路激活的一个惊人后果是GBM对诸如APO2L/TRAIL等药物的促凋亡作用产生抗性。随着雷帕霉素以及具有改善药理学特性的类似物（包括CCI-779、RAD001和AP23573）的开发，mTOR抑制已变得可行。许多研究还表明，在体外和体内将雷帕霉素类似物与APO2L/TRAIL联合使用时，具有有前景的促凋亡活性且副作用相对较轻。这些研究表明，mTOR抑制剂可与APO2L/TRAIL联合作为一种潜在的肿瘤选择性疗法。
