Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies
Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies
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DOI：
10.1002/cncr.21414
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发表时间：
2005-11-01
期刊：
影响因子：
6.2
通讯作者：
Facon, T
中科院分区：
文献类型：
--
作者：
Ludwig, H;Khayat, D;Facon, T
蛋白酶体负责细胞内蛋白质的降解，包括参与细胞周期控制和细胞凋亡调节的几种蛋白质。临床前研究表明，蛋白酶体抑制剂硼替佐米降低增殖，诱导细胞凋亡，增强细胞增殖。活性的化疗和放射治疗，并逆转化疗耐药性在各种血液和实体恶性肿瘤模型在体外和体内。硼替佐米对蛋白酶体的抑制作用通过稳定p53、p21、p27、Bax和I κ B α特异性促进肿瘤细胞凋亡，导致核因子κ B抑制。硼替佐米是第一个进入临床试验的蛋白酶体抑制剂。在两项11期试验（SUMMIT和CREST）中，发现硼替佐米单独或与地塞米松联合治疗可在复发性和/或难治性多发性骨髓瘤患者中产生持久缓解，并具有有意义的生存获益。在APEX III期试验中，硼替佐米在多发性骨髓瘤患者首次复发及以后的治疗中产生了显著的生存益处，并提高了高剂量地塞米松的缓解率。评价硼替佐米单独或与地塞米松、多柔比星、美法仑、泼尼松和/或沙利度胺联合治疗新诊断多发性骨髓瘤患者的安全性和活性的临床试验显示了令人鼓舞的结果。初步研究表明，硼替佐米可作为干细胞移植前的诱导治疗。硼替佐米对蛋白酶体的抑制作用在套细胞和其他淋巴瘤、白血病和实体恶性肿瘤（包括非小细胞肺癌）中也显示出活性和可控的毒性。硼替佐米单药治疗和联合治疗实体瘤和血液系统恶性肿瘤的进一步研究是必要的。
The proteasome is responsible for the degradation of intracellular proteins, including several involved in cell cycle control and the regulation of apoptosis Preclinical studies have shown that the proteasome inhibitor bortezomib decreases proliferation, induces apoptosis, enhances the. activity of chemotherapy and radiation, and reverses chemoresistance in a variety of hematologic and solid malignancy models in vitro and in vivo. Proteasome inhibition with bortezomib has specifically promoted apoptosis of tumor cells through the stabilization of p53, p21, p27, Bax, and I kappa B alpha, resulting in nuclear factor kappa B inhibition. Bortezomib was the first proteasome inhibitor to enter clinical trials. In two Phase 11 trials, SUMMIT and CREST, it was found that treatment with bortezomib, alone or in combination with dexamethasone, produced durable responses with meaningful survival benefits in patients with recurrent and/or refractory multiple myeloma. In the APEX Phase III trial, bortezomib produced significant survival benefits and improved response rates over high-dose dexamethasone at first recurrence and beyond in patients with multiple myeloma. Clinical trials evaluating the safety and activity of bortezomib alone or in combination regimens with dexamethasone, doxorubicin, melphalan, prednisone, and/or thalidomide in the treatment of patients with newly diagnosed multiple myeloma have shown encouraging results. Preliminary studies suggest that bortezomib may serve as induction therapy before stem cell transplantation. Proteasome inhibition with bortezomib also has shown activity with manageable toxicity in mantle cell and other lymphomas, leukemias, and solid malignancies, including nonsmall cell lung carcinoma. Further studies with bortezomib as monotherapy and in combination regimens in the treatment of solid and hematologic malignancies are warranted.