Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy
Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy
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DOI：
10.1182/blood.v96.9.2943
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发表时间：
2000-11-01
期刊：
影响因子：
20.3
通讯作者：
Anderson, KC
中科院分区：
文献类型：
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作者：
Hideshima, T;Chauhan, D;Anderson, KC
虽然沙利度胺（塔尔）最初被用于治疗多发性骨髓瘤（MM），因为它已知的抗血管生成作用，其抗MM活性的机制尚不清楚。这些研究证明了塔尔对常规治疗难治的NIM的临床活性，并描述了塔尔及其有效类似物（免疫调节药物[IMiD]）的抗肿瘤活性机制。重要的是，这些药剂通过诱导细胞凋亡或G1生长停滞直接作用于对美法仑、多柔比星和地塞米松（Dex）具有抗性的MM细胞系和患者MM细胞。此外，塔尔和IMiD增强Dex的抗MM活性，并且相反地，被白细胞介素6抑制。至于Dex，由塔尔和IMiD触发的凋亡信号传导与相关粘附灶酪氨酸激酶的活化相关。这些研究建立了在新的治疗范例中开发和测试塔尔和IMiD的框架，以靶向肿瘤细胞和微环境，克服经典的耐药性，并在这种目前无法治愈的疾病中实现改善的结果。(C)2000年，美国血液学会。
Although thalidomide (Thal) was initially used to treat multiple myeloma (MM) because of its known antiangiogenic effects, the mechanism of its anti-MM activity is unclear. These studies demonstrate clinical activity of Thal against NIM that is refractory to conventional therapy and delineate mechanisms of anti-tumor activity of Thal and its potent analogs (immunomodulatory drugs [IMiDs]). Importantly, these agents act directly, by inducing apoptosis or G1 growth arrest, in MM cell lines and in patient MM cells that are resistant to melphalan, doxorubicin, and dexamethasone (Dex), Moreover, Thal and the IMiDs enhance the anti-MM activity of Dex and, conversely, are inhibited by interleukin 6. As for Dex, apoptotic signaling triggered by Thal and the IMiDs is associated with activation of related adhesion focal tyrosine kinase, These studies establish the framework for the development and testing of Thal and the IMiDs in a new treatment paradigm to target both the tumor cell and the micro-environment, overcome classical drug resistance, and achieve improved outcome in this presently incurable disease. (C) 2000 by The American Society of Hematology.