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首页> 外文期刊>Drugs of today: Medicamentos de actualidad >Preclinical and clinical development of the proteasome inhibitor bortezomib in cancer treatment.
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Preclinical and clinical development of the proteasome inhibitor bortezomib in cancer treatment.

机译：蛋白酶体抑制剂硼替佐米在癌症治疗中的临床前和临床开发。

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The proteasome is a ubiquitous enzyme complex that plays a critical role in the degradation of many proteins involved in cell cycle regulation, apoptosis and angiogenesis. Since these pathways are fundamental for cell survival and proliferation, particularly in cancer cells, the inhibition of proteasome is an attractive potential anticancer therapy. The present review will focus on the proteasome inhibitor bortezomib (Velcade(TM), formerly PS-341; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA). Bortezomib is an extremely potent and selective proteasome inhibitor that shows strong activity in in vitro and in vivo laboratory studies against many solid and hematologic tumor types. Moreover, bortezomib, mainly by inhibition of the NF-kappaB pathway, has a chemosensitizing effect when administered together with other antitumoral drugs. Based on these results, bortezomib entered clinical phase I trials, alone or in combination with chemotherapy, that showed good tolerance at doses that achieved a desired degree of proteasome inhibition. Phase II studies showed high response rates in refractory multiple myeloma patients, which led to the accelerated approval of bortezomib by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for this indication. A phase III trial comparing bortezomib with dexamethasone in refractory/ relapsed multiple myeloma patients had to be halted due to a survival advantage in the bortezomib arm. Additional studies are focusing on the potential benefit of bortezomib in newly diagnosed multiple myeloma patients. In other solid and hematological malignancies, phase II studies with bortezomib alone or in combination with other agents are ongoing. Encouraging results, particularly in lung cancer and lymphoma, have been observed. The critical molecules or genes responsible for tumor sensitivity to bortezomib continue to be evaluated using novel technologies. (c) 2005 Prous Science. All rights reserved.
机译：蛋白酶体是一种普遍存在的酶复合物，在许多参与细胞周期调节，细胞凋亡和血管生成的蛋白质的降解中起关键作用。由于这些途径是细胞存活和增殖的基础，特别是在癌细胞中，因此蛋白酶体的抑制是有吸引力的潜在抗癌治疗方法。本综述将集中于蛋白酶体抑制剂硼替佐米（Velcade TM，以前为PS-341; Millennium Pharmaceuticals，Inc.，Cambridge，MA，USA）。硼替佐米是一种非常有效的选择性蛋白酶体抑制剂，在体外和体内实验室研究中针对多种实体和血液肿瘤类型均显示出强大的活性。此外，硼替佐米主要通过抑制NF-κB途径，与其他抗肿瘤药物一起给药时具有化学增敏作用。基于这些结果，硼替佐米单独或与化学疗法一起进入了临床I期试验，在达到所需程度的蛋白酶体抑制作用的剂量下，它显示出良好的耐受性。 II期研究显示，难治性多发性骨髓瘤患者反应率高，这导致美国食品药品监督管理局（FDA）和欧洲药品管理局（EMEA）加快了硼替佐米的批准。由于硼替佐米组具有生存优势，因此必须停止一项硼替佐米与地塞米松治疗难治/复发性多发性骨髓瘤患者的III期试验。其他研究集中在硼替佐米在新诊断的多发性骨髓瘤患者中的潜在益处。在其他实体和血液系统恶性肿瘤中，正在进行单独使用硼替佐米或与其他药物合用的II期研究。已经观察到令人鼓舞的结果，尤其是在肺癌和淋巴瘤中。继续使用新技术评估导致肿瘤对硼替佐米敏感的关键分子或基因。 （c）2005 Prous科学。版权所有。

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