Orlowski Robert Z
University of North Carolina at Chapel Hill, 22-003 Lineberger Comprehensive Cancer Center, CB # 7295, Mason Farm Road, Chapel Hill, NC 27599-7295, USA.
Expert Rev Anticancer Ther. 2004 Apr;4(2):171-9. doi: 10.1586/14737140.4.2.171.
The multicatalytic proteinase complex, or proteasome, is responsible for the majority of regulated eukaryotic protein turnover through the ubiquitin-proteasome pathway. Bortezomib (Velcade, Millennium Pharmaceuticals, Inc.), the first drug specifically designed to target the proteasome, has recently entered the clinical arena. Previous preclinical studies showed that bortezomib had a unique cytotoxicity profile and that proteasome inhibition in vivo could be achieved safely with concomitant antitumor efficacy. In clinical studies, bortezomib has shown remarkable single-agent activity against relapsed and refractory multiple myeloma in both Phase I and II trials. Based on the latter, bortezomib has been approved by the US Food and Drug Administration for patients who have received two prior regimens and progressed on the second of these. Early results with bortezomib as a front-line therapy for multiple myeloma have shown a high response rate and further studies are ongoing. Preclinical studies support the possibility that modulation of proteasome function has great potential as a strategy for chemosensitization. Preliminary clinical trial results suggest that combinations using standard chemotherapeutics with bortezomib may have higher response rates in multiple myeloma than bortezomib as a single agent. Furthermore, these combinations may be able to recapture a response in patients whose disease was previously resistant to the standard agent, or bortezomib, or both. If borne out by additional studies, these results suggest that older treatment paradigms, in which drugs were used once but then discarded from the armamentarium upon disease progression, may need to be reassessed. Bortezomib may provide significant benefits to patients both alone and in combination with other agents and at several time points during the natural history of multiple myeloma.
多催化蛋白酶复合体，即蛋白酶体，通过泛素-蛋白酶体途径负责大多数受调控的真核生物蛋白质周转。硼替佐米（万珂，千年制药公司）是首个专门设计用于靶向蛋白酶体的药物，最近已进入临床应用。先前的临床前研究表明，硼替佐米具有独特的细胞毒性特征，并且在体内可安全地实现蛋白酶体抑制，同时具有抗肿瘤疗效。在临床研究中，硼替佐米在I期和II期试验中均显示出对复发和难治性多发性骨髓瘤具有显著的单药活性。基于后者，硼替佐米已被美国食品药品监督管理局批准用于接受过两种先前治疗方案且在第二种方案中病情进展的患者。硼替佐米作为多发性骨髓瘤一线治疗的早期结果显示出高缓解率，进一步的研究正在进行中。临床前研究支持蛋白酶体功能调节作为化学增敏策略具有巨大潜力的可能性。初步临床试验结果表明，标准化疗药物与硼替佐米联合使用在多发性骨髓瘤中的缓解率可能高于硼替佐米单药使用。此外，这些联合用药可能能够使先前对标准药物、硼替佐米或两者均耐药的患者重新获得缓解。如果更多研究证实这些结果，这表明旧的治疗模式，即药物一旦使用但在疾病进展时就从药物库中摒弃，可能需要重新评估。硼替佐米无论是单独使用还是与其他药物联合使用，以及在多发性骨髓瘤自然病程的多个时间点，都可能为患者带来显著益处。
