The immunoproteasome as a target in hematologic malignancies.
The immunoproteasome as a target in hematologic malignancies.
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DOI：
10.1053/j.seminhematol.2012.04.003
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发表时间：
2012-07
影响因子：
3.6
通讯作者：
Orlowski RZ
中科院分区：
文献类型：
--
作者：
Kuhn DJ;Orlowski RZ
用一流的小分子抑制剂硼替佐米抑制蛋白酶体功能是治疗几种血液恶性肿瘤（包括多发性骨髓瘤和套细胞淋巴瘤）的合理治疗策略。第二代抑制剂，如卡非佐米、伊沙佐米和马里扎利汀，与硼替佐米一样，靶向组成型蛋白酶体和免疫蛋白酶体，也在临床试验中，并显示出令人鼓舞的活性。虽然这些药物的疗效已得到充分证明，但与其使用相关的毒性，如周围神经病变和胃肠道效应，可能需要减少剂量甚至停药，这可能会妨碍其抗肿瘤作用。这些发现表明，有可能通过仅特异性靶向免疫蛋白酶体来提高这类药物的治疗指数。由于免疫蛋白酶体是淋巴源性细胞中发现的独特靶标，免疫蛋白酶体特异性抑制剂（IPSI）可以保持疗效，同时减少治疗后出现的毒性，因为它们可以避免其他组织的免疫蛋白酶体表达很少或没有。这篇综述讨论了IPSI的发展现状，以及使用此类药物治疗血液系统恶性肿瘤的潜力。
Suppression of proteasome function with the first-in-class small molecule inhibitor bortezomib is a rational therapeutic strategy against several hematologic malignancies, including multiple myeloma and mantle cell lymphoma. Second generation inhibitors such as carfilzomib, ixazomib, and marizomib that, like bortezomib, target both the constitutive proteasome and the immunoproteasome, are also in clinical trials and showing encouraging activity. While the efficacy of these agents is well documented, toxicities associated with their use, such as peripheral neuropathy and gastrointestinal effects, can necessitate dose reductions or even discontinuations, possibly hampering their anti-neoplastic effects. These findings suggested that it could be possible to improve the therapeutic index of this class of drugs by specifically targeting only the immunoproteasome. Since the immunoproteasome is a unique target found in lymphoid-derived cells, immunoproteasome-specific inhibitors (IPSIs) could preserve efficacy while reducing treatment-emergent toxicities since they would spare other tissues with little to no immunoproteasome expression. This review discusses the current state of development of IPSIs, and the potential of using such agents for the treatment of hematologic malignancies.
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影响因子：
82.9
作者：
Muchamuel, Tony;Basler, Michael;Groettrup, Marcus
通讯作者：
Groettrup, Marcus
影响因子：
56.9
作者：
LOWE, J;STOCK, D;HUBER, R
通讯作者：
HUBER, R
影响因子：
--
作者：
Ichikawa HT;Conley T;Muchamuel T;Jiang J;Lee S;Owen T;Barnard J;Nevarez S;Goldman BI;Kirk CJ;Looney RJ;Anolik JH
通讯作者：
Anolik JH
DOI：
10.1084/jem.179.3.901
发表时间：
1994-03-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Boes B;Hengel H;Ruppert T;Multhaup G;Koszinowski UH;Kloetzel PM
通讯作者：
Kloetzel PM
影响因子：
20.3
作者：
Parlati, Francesco;Lee, Susan J.;Bennett, Mark K.
通讯作者：
Bennett, Mark K.