蛋白酶体抑制剂治疗多发性骨髓瘤现状

 【摘要】　多发性骨髓瘤（MM）是骨髓浆细胞克隆性增殖的血液系统恶性肿瘤，其发病率约占血液系统肿瘤的10 %。蛋白酶体是细胞内的一种复合酶，它可以降解泛素标记的蛋白，调节细胞内蛋白水平，在保持细胞内环境的稳定中起重要作用。近年来，新型靶向药物蛋白酶体抑制剂的应用，使MM的治疗取得了很大的进展，进一步改善了骨髓瘤的治疗疗效。硼替佐米是首个获美国食品和药物管理局（FDA）批准用于MM临床治疗的蛋白酶体抑制剂，它能可逆地抑制26S蛋白酶体糜蛋白样活性。但是，大多数硼替佐米初治后缓解的患者因产生耐药而最终导致疾病复发，因此，人们开始寻找与硼替佐米作用机制不同的蛋白酶体抑制剂。目前研究发现了一些能特异地结合蛋白酶体活性位点并且不可逆的抑制其功能的抑制剂，这些药物正在进行相关的临床试验。对已用于治疗MM的蛋白酶体抑制剂硼替佐米进行讨论，并对正在进行前期临床试验的新型蛋白酶体抑制剂进行概述，旨在解决硼替佐米的耐药性问题。

Status of proteasome inhibitors in the treatment of multiple myeloma

【Abstract】　Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of bone marrow plasmacytes. It accounts for 10 % of all hematological malignancies. The proteasome, an intracellular enzyme complex that degrades ubiquitin-tagged proteins to regulate protein levels within the cell, plays an important role in maintaining cellular homeostasis. Proteasome inhibitors proved to be significantly effective in the clinical treatment of MM. In recent years, the application of the proteasome inhibitor has led to increased survival rates in MM patients. Bortezomib is the first proteasome inhibitor that has been approved by the US Food and Drug Administration due to its ability to reversibly inhibit the 26 s proteasome functions. Despite the fact that Bortezomib improves medical treatment, many patients experience difficulty responding to this drug and some patients who do respond eventually relapse. These results have led researchers to investigate new proteasome inhibitors with mechanisms different from those of Bortezomib. Some drugs that bind to the active site of the proteasome and irreversibly inhibit the complex have recently been developed and are currently being tested in advanced clinical trials. Here, we will elaborate on the proteasome inhibitors targeting MM and focus on newly discovered inhibitors that may overcome the resistance to Bortezomib.