Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Biochem Soc Trans. 2010 Feb;38(Pt 1):14-20. doi: 10.1042/BST0380014.
The observation that tumour cells are more sensitive to pharmacological inhibition of the proteasome than normal cells has led to the development of the proteasome inhibitor bortezomib. To date, this is the only proteasome inhibitor that has been approved for clinical use. The clinical success of bortezomib, combined with the occurrence of adverse effects and the development of clinical resistance against this compound, has initiated the development of a broad range of second-generation proteasome inhibitors as well as of assays that can be used to establish a relationship between the extent and type of proteasome inhibition and the effectiveness of a particular drug. In the present paper, we discuss new strategies that may be used in the future to overcome drug resistance and to broaden the use of proteasome inhibitors for the treatment of both cancer and infectious and autoimmune disease.
肿瘤细胞比正常细胞对蛋白酶体的药理抑制更为敏感，这一观察结果导致了蛋白酶体抑制剂硼替佐米的开发。迄今为止，这是唯一一种已被批准用于临床的蛋白酶体抑制剂。硼替佐米的临床成功，加上不良反应的发生和对这种化合物的临床耐药性的发展，促使人们开发了广泛的第二代蛋白酶体抑制剂以及可用于建立蛋白酶体抑制程度和类型与特定药物有效性之间关系的检测方法。在本文中，我们讨论了未来可能用于克服耐药性以及拓宽蛋白酶体抑制剂在癌症以及感染和自身免疫性疾病治疗中的应用的新策略。
