Document Detail

The immunoproteasome as a target in hematologic malignancies.
MedLine Citation:
PMID:  22726549     Owner:  NLM     Status:  MEDLINE    
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.
Deborah J Kuhn; Robert Z Orlowski
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Seminars in hematology     Volume:  49     ISSN:  1532-8686     ISO Abbreviation:  Semin. Hematol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-25     Completed Date:  2013-06-10     Revised Date:  2014-07-07    
Medline Journal Info:
Nlm Unique ID:  0404514     Medline TA:  Semin Hematol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  258-62     Citation Subset:  IM    
Copyright Information:
Copyright © 2012. Published by Elsevier Inc.
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MeSH Terms
Antineoplastic Agents / pharmacology*,  therapeutic use
Hematologic Neoplasms / drug therapy*,  enzymology*,  immunology,  pathology
Proteasome Endopeptidase Complex / immunology*,  metabolism*
Proteasome Inhibitors / pharmacology*,  therapeutic use
Grant Support
1K99 CA149140/CA/NCI NIH HHS; K99 CA149140/CA/NCI NIH HHS; P30 CA016672/CA/NCI NIH HHS; P50 CA142509/CA/NCI NIH HHS; P50 CA142509/CA/NCI NIH HHS; U10 CA032102/CA/NCI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/Proteasome Inhibitors; EC Endopeptidase Complex

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