Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma
Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma
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DOI：
10.1038/sj.leu.2404471
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发表时间：
2007-02-01
期刊：
影响因子：
11.4
通讯作者：
Koeffler, H. P.
中科院分区：
文献类型：
--
作者：
Haritunians, T.;Mori, A.;Koeffler, H. P.
套细胞淋巴瘤（MCL）是一种侵袭性的B细胞非霍奇金淋巴瘤，平均生存期仅为3-5年，治疗选择不理想。MCL的特征是平衡易位t（11;14）（q13; q32），导致细胞周期蛋白D1（一种受PI 3 K/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路调节的G（1）细胞周期蛋白）过表达。由于需要改进MCL的治疗并且mTOR途径可能参与其病理生理学，因此研究了mTOR抑制剂RAD 001（依维莫司）对三种MCL细胞系的抗增殖作用。与稀释剂对照细胞相比，作为单一药剂，RAD 001抑制MCL细胞系（Jeko 1、SP 49和NCEB 1）中的增殖约40-65%。这与G（1）细胞周期停滞和mTOR下游靶点4 E-BP 1磷酸化减少有关。此外，联合药物研究显示，RAD 001和几种次要药物，包括多柔比星、长春新碱或利妥昔单抗（标准MCL方案的组分），以及紫杉醇、伏立诺他和硼替佐米，主要具有协同细胞毒性。这些数据表明，单一试剂RAD 001在体外有效抑制MCL细胞的生长，并且与第二试剂的组合研究进一步证明了协同细胞毒性。因此，这些发现支持了未来RAD 001治疗MCL的临床研究。
Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin's lymphoma, with a mean survival of only 3-5 years and suboptimal therapeutic options. MCL is characterized by a balanced translocation t(11;14)( q13; q32), resulting in overexpression of cyclin D1, a G(1) cyclin regulated by the PI3K/Akt/mammalian target of rapamycin ( mTOR) signaling pathway. As improved therapy for MCL is required and the mTOR pathway may be involved in its pathophysiology, the antiproliferative effects of RAD001 ( everolimus), an mTOR inhibitor, against three MCL cell lines were investigated. As a single agent, RAD001 inhibited proliferation in MCL cell lines (Jeko1, SP49 and NCEB1) approximately 40-65% compared to diluent control cells. This was associated with G(1) cell-cycle arrest and reduced phosphorylation of the mTOR downstream target, 4E-BP1. Furthermore, combination drug studies revealed predominantly synergistic cytotoxicity with RAD001 and several secondary agents, including doxorubicin, vincristine or rituximab ( components of the standard MCL regimen), as well as paclitaxel, vorinostat and bortezomib. These data indicate that single agent RAD001 is effective in inhibiting growth of MCL cells in vitro and combination studies with secondary agents further demonstrate synergistic cytotoxicity. Thus, these findings support future clinical studies of RAD001 in the treatment of MCL.