文章：

多发性骨髓瘤新治疗方法的分子机制

Molecular mechanisms of novel therapeutic approaches for multiple myeloma

原文发布日期：2002-12-01

DOI: 10.1038/nrc952

类型: Review Article

开放获取: 否

要点：

1. Multiple myeloma (MM) is a B-cell malignancy that is characterized by an excess of monotypic plasma cells in the bone marrow (BM) that is in association with monoclonal protein in serum and/or urine, decreased normal immunoglobulin levels and lytic bone disease.
2. Although conventional therapies can extend patient survival to an average of 3–4 years and high-dose therapy that is followed by autologous stem-cell transplantation can modestly prolong the survival to 4–5 years, MM remains largely incurable.
3. MM cells home to the host bone marrow by binding to adhesion molecules on extracellular matrix proteins and bone-marrow stromal cells. This localizes tumour cells in the BM microenvironment and confers cell-adhesion-mediated drug resistance. Cytokines (such as interleukin-6 (IL-6), insulin-like growth factor 1 (IGF1), tumour necrosis factor-α (TNF-α) and stromal-cell-derived factor-1α (SDF-1α)) mediate MM cell growth, survival and migration and, following treatment, the development of drug resistance in the bone-marrow microenvironment.
4. MM cell proliferation, survival and, following treatment, drug resistance by anti-apoptotic mechanisms are mediated through the RAF/mitogen-activated protein kinase (MAPK) kinase (MEK)/p42/p44 MAPK, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and phosphatidylinositol (PI3K)/AKT signalling cascades, respectively.
5. Novel biologically based treatments (such as thalidomide/immunomodulatory derivatives (IMiDs) and PS-341) target not only the MM cell, but also the interaction between MM cells and the host or the BM microenvironment, and can overcome conventional drug resistance in vitro and in vivo in preclinical models.
6. Thalidomide/IMiDs and PS-341 have already shown remarkable activity against MM in Phase I/II clinical trials of patients with relapsed and refractory disease, with manageable toxicity profiles. These drugs, when used with conventional and/or other novel therapies, represent a new treatment model to improve patient outcome in MM.
7. Ongoing gene microarray and proteomic studies of these new agents are identifying molecular targets that confer drug sensitivity versus resistance, to derive more selective targeted therapies for validation in animal models and the translation to the clinic in clinical trials.

要点翻译：

1. 多发性骨髓瘤（MM）是一种B细胞恶性肿瘤，其特征为骨髓中单克隆浆细胞异常增殖，伴随血清和/或尿液中出现单克隆蛋白、正常免疫球蛋白水平降低以及溶骨性病变。
2. 尽管常规治疗可将患者生存期延长至平均3-4年，自体干细胞移植支持的大剂量治疗可适度延长生存期至4-5年，但该疾病目前仍基本无法治愈。
3. 骨髓瘤细胞通过结合细胞外基质蛋白和骨髓基质细胞上的黏附分子归巢至宿主骨髓。这种定位使肿瘤细胞集中于骨髓微环境中，并引发细胞黏附介导的耐药性。细胞因子（如白细胞介素-6（IL-6）、胰岛素样生长因子1（IGF1）、肿瘤坏死因子-α（TNF-α）和基质细胞衍生因子-1α（SDF-1α））不仅介导骨髓瘤细胞的生长、存活和迁移，还在治疗后诱导骨髓微环境中耐药性的产生。
4. 通过抗凋亡机制，RAF/丝裂原活化蛋白激酶（MAPK）激酶（MEK）/p42/p44 MAPK、Janus激酶（JAK）/信号转导与转录激活因子（STAT）以及磷脂酰肌醇3激酶（PI3K）/AKT信号通路分别介导了骨髓瘤细胞的增殖、存活及治疗后耐药性的形成。
5. 新型生物靶向治疗药物（如沙利度胺/免疫调节衍生物（IMiDs）和PS-341）不仅靶向骨髓瘤细胞本身，还针对骨髓瘤细胞与宿主或骨髓微环境间的相互作用，在临床前模型中能够克服体外和体内的常规耐药性。
6. 在复发难治性患者的I/II期临床试验中，沙利度胺/IMiDs和PS-341已显示出显著抗骨髓瘤活性，且毒性可控。这些药物与传统治疗和/或其他新型疗法联用，为改善多发性骨髓瘤患者预后提供了新的治疗模式。
7. 针对这些新药的基因微阵列和蛋白质组学研究正在持续进行，通过识别导致药物敏感性与耐药性的分子靶点，将推动更具选择性的靶向治疗方案的开发，并在动物模型中验证后通过临床试验转化为临床实践。

英文摘要：

Multiple myeloma remains largely incurable despite conventional and high-dose therapies, and so novel biologically based treatment approaches are urgently required. Recent studies have characterized the molecular mechanisms by which multiple myeloma cell–host bone-marrow interactions regulate tumour cell growth, survival and migration in the bone-marrow microenvironment. These studies have not only enhanced our understanding of disease pathogenesis, but have also provided the framework for a new treatment model that targets the multiple myeloma cell in its bone-marrow microenvironment to overcome drug resistance and improve patient outcome.

摘要翻译： 

多发性骨髓瘤尽管接受了常规和大剂量化疗，基本上仍无法治愈，因此迫切需要新的生物学治疗手段。最新研究阐明了骨髓瘤细胞与宿主骨髓之间相互作用在骨髓微环境中调控肿瘤细胞生长、存活和迁移的分子机制。这些研究不仅加深了我们对疾病发病机制的理解，也为一种新的治疗模式提供了框架：在骨髓微环境中靶向骨髓瘤细胞，以克服耐药并改善患者预后。

原文链接：

Molecular mechanisms of novel therapeutic approaches for multiple myeloma