Anderson Kenneth C
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Semin Hematol. 2005 Oct;42(4 Suppl 4):S3-8. doi: 10.1053/j.seminhematol.2005.10.001.
Multiple myeloma is a B-cell malignancy characterized by an excess of monotypic plasma cells in the bone marrow. The molecular mechanisms that are involved in disease progression depend on the interaction between the multiple myeloma cells and the bone microenvironment. Because these mechanisms have been well characterized, it is possible to develop regimens that are more specific to pathways involved in the pathogenesis of multiple myeloma than is typical for conventional chemotherapy in disease management. Thalidomide and immunomodulatory drugs (IMiDs) have now been shown to block several pathways important for disease progression in multiple myeloma. First established as agents with antiangiogenic properties, thalidomide and IMiDs inhibit the production of interleukin (IL)-6, which is a growth factor for the proliferation of myeloma cells. In addition, they activate apoptotic pathways through caspase 8-mediated cell death. At the mitochondrial level, they are responsible for c-jun terminal kinase (JNK)-dependent release of cytochrome-c and Smac into the cytosol of cells, where they regulate the activity of molecules that affect apoptosis. By activating T cells to produce IL-2, thalidomide and IMiDs alter natural killer (NK) cell numbers and function, thus augmenting the activity of NK-dependent cytotoxicity. Data delineating these events have been derived from experiments done in resistant and sensitive multiple myeloma cell lines. Although thalidomide and IMiDs demonstrate similar biologic activities, IMiDs are more potent than thalidomide and achieve responses at lower doses. Lenalidomide, a thalidomide derivative, has also been shown to have a different toxicity profile. Our understanding of the mechanism of action of these agents has provided a platform for exciting clinical trials evaluating combinations of thalidomide and lenalidomide with both conventional chemotherapy and newer targeted agents.
多发性骨髓瘤是一种B细胞恶性肿瘤，其特征是骨髓中存在过量的单克隆浆细胞。疾病进展所涉及的分子机制取决于多发性骨髓瘤细胞与骨微环境之间的相互作用。由于这些机制已得到充分表征，因此有可能开发出比疾病管理中的传统化疗更具多发性骨髓瘤发病机制相关途径特异性的治疗方案。沙利度胺和免疫调节药物（IMiDs）现已被证明可阻断对多发性骨髓瘤疾病进展至关重要的几种途径。沙利度胺和IMiDs最初被确立为具有抗血管生成特性的药物，它们可抑制白细胞介素（IL）-6的产生，IL-6是骨髓瘤细胞增殖的生长因子。此外，它们通过半胱天冬酶8介导的细胞死亡激活凋亡途径。在线粒体水平，它们负责c-jun末端激酶（JNK）依赖性地将细胞色素c和Smac释放到细胞胞质溶胶中，在那里它们调节影响细胞凋亡的分子的活性。通过激活T细胞产生IL-2，沙利度胺和IMiDs改变自然杀伤（NK）细胞数量和功能，从而增强NK依赖性细胞毒性的活性。描述这些事件的数据来自对耐药和敏感的多发性骨髓瘤细胞系进行的实验。尽管沙利度胺和IMiDs表现出相似的生物学活性，但IMiDs比沙利度胺更有效，且在较低剂量下即可产生反应。来那度胺，一种沙利度胺衍生物，也已被证明具有不同的毒性特征。我们对这些药物作用机制的理解为评估沙利度胺和来那度胺与传统化疗和新型靶向药物联合使用的激动人心的临床试验提供了一个平台。
