Clinical update: proteasome inhibitors in solid tumors
Clinical update: proteasome inhibitors in solid tumors
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DOI：
10.1016/s0305-7372(03)00082-3
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发表时间：
2003-05-01
影响因子：
11.8
通讯作者：
Lenz, HJ
中科院分区：
文献类型：
--
作者：
Lenz, HJ
蛋白酶体在调节细胞周期、肿瘤生长和转移中起关键作用。硼替佐米（万珂;以前称为PS-341、LDP-341、MLN 341）是一种新型二肽硼酸，是第一种进入临床试验的蛋白酶体抑制剂。临床前研究表明，通过预防IkappaB降解，硼替佐米可以阻断化疗诱导的NF-κ B活化并增加对化疗药物的凋亡反应。硼替佐米似乎还增加了p21和p27以及转录因子p53的稳定性。在乳腺、肺、胰腺和卵巢肿瘤类型的临床前模型中，硼替佐米抑制肿瘤生长并显示出抗血管生成特性。硼替佐米与标准化疗药物（如伊立替康、吉西他滨和多西他赛）联合使用时表现出最大活性，表明其在克服常规化疗耐药性方面具有潜在的相加/协同作用。来自早期临床试验的初步数据表明，硼替佐米可以以有效剂量与标准剂量的化疗联合使用，毒性可控。已经观察到反应，并且在联合药物试验中没有显示出相加毒性的证据。(C)2003爱思唯尔科技有限公司版权所有。
The proteasome plays a critical role in regulating the cell cycle, neoplastic growth, and metastasis. Bortezomib (VELCADE; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid that is the first proteasome inhibitor to have progressed to clinical trials. Preclinical research has shown that through the prevention of IkappaB degradation, bortezomib may block chemotherapy-induced NF-kappaB activation and augment the apoptotic response to chemotherapeutic agents. Bortezomib also appeared to increase the stabilization of p21 and p27, as well as transcription factor p53. In preclinical models of breast, lung, pancreatic, and ovarian tumor types, bortezomib inhibited tumor growth and demonstrated anti-angiogenic properties. Bortezomib exhibited the greatest activity when combined with standard chemotherapeutic agents, such as irinotecan, gemcitabine, and docetaxel, suggesting its potential additive/syngeristic role in overcoming resistance to conventional chemotherapy. Preliminary data from early clinical trials suggest that bortezomib can be given at pharmacologically active doses in combination with standard doses of chemotherapy with manageable toxicities. Responses have been seen and no evidence of additive toxicity has been exhibited in combination agent trials. (C) 2003 Elsevier Science Ltd. All rights reserved.