The proteasome has been regarded as a major target for antitumor therapy in selected tumor types (i.e., multiple myeloma). Available evidence suggests that targeting the proteasome with selective compounds can represent an excellent approach for modulating the response to antitumor agents including both conventional cytotoxic agents and target-specific agents. In fact, promising drug interaction data showing synergistic effects have been reported in cellular studies, both in multiple myeloma and in solid tumors. The mechanistic bases of improved efficacy of drug combinations including bortezomib or other proteasome inhibitors and conventional cytotoxic agents have been in part unravelled and involve the capability of proteasome inhibitors to interfere with the stability of the targets of cytotoxic agents (e.g., topoisomerase inhibitors) as well as with cellular protective pathways (e.g., DNA repair and NF-kB-regulated gene expression). Moreover, the synergistic interaction of proteasome inhibitors and target-specific agents implicates a variety of mechanisms linked to the specific target (e.g., histone deacetylase) modulated by the tailored drug used in combination with the proteasome inhibitor. Several clinical studies are ongoing in an attempt to define drug combination approaches that enhance the efficacy of antitumor treatments. Considering the fast moving field of preclinical research regarding proteasome inhibition, a major contribution to the understanding of the bases of tumor response to treatment with proteasome inhibitors is expected.

译文

蛋白酶体被认为是某些肿瘤类型 (即多发性骨髓瘤) 抗肿瘤治疗的主要靶标。现有证据表明,用选择性化合物靶向蛋白酶体可以代表调节对抗肿瘤剂 (包括常规细胞毒性剂和靶标特异性剂) 的反应的极好方法。实际上,在多发性骨髓瘤和实体瘤的细胞研究中已经报道了显示协同作用的有希望的药物相互作用数据。改善药物组合 (包括硼替佐米或其他蛋白酶体抑制剂和常规细胞毒性剂) 功效的机理基础已部分阐明,并涉及蛋白酶体抑制剂干扰细胞毒性剂靶标稳定性的能力 (例如,拓扑异构酶抑制剂) 以及细胞保护途径 (例如,DNA修复和NF-kB调节的基因表达)。此外,蛋白酶体抑制剂和靶标特异性试剂的协同相互作用涉及多种机制,这些机制与由与蛋白酶体抑制剂组合使用的定制药物调节的特定靶标 (例如组蛋白脱乙酰基酶) 有关。正在进行一些临床研究,以尝试定义可增强抗肿瘤治疗功效的药物组合方法。考虑到有关蛋白酶体抑制的临床前研究的快速发展领域,有望对理解蛋白酶体抑制剂治疗的肿瘤反应基础做出重大贡献。

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