Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies.
Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies.
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DOI：
10.1111/j.1365-2141.2009.07657.x
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发表时间：
2009-06
影响因子：
6.5
通讯作者：
Brown VI
中科院分区：
文献类型：
--
作者：
Teachey DT;Grupp SA;Brown VI
哺乳动物雷帕霉素靶蛋白（mTOR）是一种丝氨酸/苏氨酸激酶，通过与PI 3 K/AKT、ras、TCL 1和BCR/ABL等多种信号通路相互作用，在细胞生长、蛋白质合成和细胞周期进程中发挥重要调节作用。因此，mTOR抑制剂，一类最初作为免疫抑制剂开发的信号转导抑制剂，正在许多血液恶性肿瘤的临床前模型和临床试验中进行研究。西罗莫司和第二代mTOR抑制剂（如替西罗莫司和依维莫司）是安全的且耐受性相对良好，使得它们作为单一药剂或与常规细胞毒素和其他靶向疗法组合具有潜在吸引力。有希望的早期临床数据表明mTOR抑制剂在许多血液病中具有活性，包括急性淋巴细胞白血病、慢性髓细胞性白血病、套细胞淋巴瘤、间变性大细胞淋巴瘤和淋巴增生性疾病。本文综述了mTOR抑制剂在各种血液病中的应用原理，重点介绍了其在白血病中的应用。
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell growth, protein synthesis, and cell-cycle progression through interactions with a number of signaling pathways, including PI3K/AKT, ras, TCL1, and BCR/ABL. Many haematologic malignancies have aberrant activation of the mTOR and related signaling pathways. Accordingly, mTOR inhibitors, a class of signal transduction inhibitors that were originally developed as immunosuppressive agents, are being investigated in preclinical models and clinical trials for a number of haematologic malignancies. Sirolimus and second generation mTOR inhibitors such as temsirolimus and everolimus, are safe and relatively well-tolerated, making them potentially attractive as single agents or in combination with conventional cytotoxics and other targeted therapies. Promising early clinical data suggests activity of mTOR inhibitors in a number of haematologic diseases, including acute lymphoblastic leukemia, chronic myelogenous leukemia, mantle cell lymphoma, anaplastic large cell lymphoma, and lymphoproliferative disorders. This review describes the rationale for using mTOR inhibitors in a variety of haematologic diseases with a focus on their use in leukemia.
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