Orlowski Robert Z, Kuhn Deborah J
Department of Lymphoma/Myeloma, Division of Cancer Medicine, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2008 Mar 15;14(6):1649-57. doi: 10.1158/1078-0432.CCR-07-2218.
The ubiquitin-proteasome pathway is involved in intracellular protein turnover, and its function is crucial to cellular homeostasis. First synthesized as probes of proteolytic processes, proteasome inhibitors began to be thought of as potential drug candidates when they were found to induce programmed cell death preferentially in transformed cells. They made their first leap into the clinic to be tested as therapeutic agents 10 years ago, and since then, great strides have been made in defining their mechanisms of action, their clinical efficacy and toxicity, and some of their limitations in the form of resistance pathways. Validation of the ubiquitin-proteasome pathway as a target for cancer therapy has come in the form of approvals of the first such inhibitor, bortezomib, for relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this agent has become a standard of care. Lessons learned from this first-in-class agent are now being applied to the development of a new generation of proteasome inhibitors that hold the promise of efficacy in bortezomib-resistant disease and possibly in a broader spectrum of diseases. This saga provides a salient example of the promise of translational medicine and a paradigm by which other agents may be successfully brought from the bench to the bedside.
泛素-蛋白酶体途径参与细胞内蛋白质周转，其功能对细胞稳态至关重要。蛋白酶体抑制剂最初作为蛋白水解过程的探针被合成，当发现它们能优先诱导转化细胞发生程序性细胞死亡时，开始被视为潜在的候选药物。10年前，它们首次进入临床作为治疗药物进行测试，从那时起，在确定其作用机制、临床疗效和毒性以及耐药途径形式的一些局限性方面取得了巨大进展。泛素-蛋白酶体途径作为癌症治疗靶点的验证，表现为首个此类抑制剂硼替佐米被批准用于复发/难治性多发性骨髓瘤和套细胞淋巴瘤，该药已成为这两种疾病的标准治疗药物。从这类首创药物中吸取的经验教训，目前正应用于新一代蛋白酶体抑制剂的研发，这些抑制剂有望对硼替佐米耐药的疾病有效，甚至可能对更广泛的疾病有效。这个历程为转化医学的前景提供了一个突出的例子，也是一个可将其他药物成功从实验室推向临床应用的范例。
