CAJ | 학술논문

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.
다발성골수류(MM)시골수장세포극륭성증식적혈액계통악성종류,기발병솔약점혈액계통종류적10％.단백매체시세포내적일충복합매,타가이강해범소표기적단백,조절세포내단백수평,재보지세포내배경적은정중기중요작용.근년래,신형파향약물단백매체억제제적응용,사MM적치료취득료흔대적진전,진일보개선료골수류적치료료효.붕체좌미시수개획미국식품화약물관리국(FDA)비준용우MM림상치료적단백매체억제제,타능가역지억제26S단백매체미단백양활성.단시,대다수붕체좌미초치후완해적환자인산생내약이최종도치질병복발,인차,인문개시심조여붕체좌미작용궤제불동적단백매체억제제.목전연구발현료일사능특이지결합단백매체활성위점병차불가역적억제기공능적억제제,저사약물정재진행상관적림상시험.대이용우치료MM적단백매체억제제붕체좌미진행토론,병대정재진행전기림상시험적신형단백매체억제제진행개술,지재해결붕체좌미적내약성문제.
Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion ofbone 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.