Raje Noopur, Kumar Shaji, Hideshima Teru, Ishitsuka Kenji, Chauhan Dharminder, Mitsiades Constantine, Podar Klaus, Le Gouill Steven, Richardson Paul, Munshi Nikhil C, Stirling David I, Antin Joseph H, Anderson Kenneth C
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, VA Boston Healthcare System and Harvard Medical School, Boston, MA 02115, USA.
Blood. 2004 Dec 15;104(13):4188-93. doi: 10.1182/blood-2004-06-2281. Epub 2004 Aug 19.
Previous studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.
既往研究已证实沙利度胺的免疫调节类似物（IMiD）CC-5013（来那度胺）在体外和体内对多发性骨髓瘤（MM）的活性。在本研究中，我们检测了特异性mTOR抑制剂雷帕霉素（雷帕鸣）与CC-5013联合应用时的抗MM活性。基于Chou-Talalay方法，CC-5013与雷帕霉素联合应用时在所有剂量范围内均获得小于1的联合指数，提示有强协同作用。重要的是，在对耐传统化疗的MM细胞系进行检测时，该联合用药能够克服耐药性。此外，该联合用药而非单独使用雷帕霉素，能够克服白细胞介素-6（IL-6）、胰岛素样生长因子-1（IGF-1）或黏附于骨髓基质细胞（BMSC）赋予MM细胞的生长优势。雷帕霉素与CC-5013联合应用可诱导MM细胞凋亡。这些药物单独及联合应用时靶向不同的信号级联反应，包括丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3'-激酶/蛋白激酶B（PI3K/Akt）途径，提示它们干扰MM生长和存活的分子机制。因此，这些研究为mTOR抑制剂与IMiD联合应用以改善MM患者预后的临床评估提供了框架。
