Document Detail


Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib.
MedLine Citation:
PMID:  15148407     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer.
Authors:
Kai Sun; Lisbeth A Welniak; Angela Panoskaltsis-Mortari; Matthew J O'Shaughnessy; Haiyan Liu; Isabel Barao; William Riordan; Raquel Sitcheran; Christian Wysocki; Jonathan S Serody; Bruce R Blazar; Thomas J Sayers; William J Murphy
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-05-17
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  101     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-05-26     Completed Date:  2004-07-09     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8120-5     Citation Subset:  IM    
Affiliation:
Department of Microbiology and Immunology, University of Nevada, Reno, NV 89557, USA.
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MeSH Terms
Descriptor/Qualifier:
Acute Disease / therapy
Animals
Bone Marrow Transplantation / adverse effects,  immunology
Boronic Acids / adverse effects,  pharmacology*,  therapeutic use
Cell Line, Tumor
Female
Graft vs Host Disease / drug therapy,  immunology*,  prevention & control*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
NF-kappa B / metabolism
Protease Inhibitors / adverse effects,  pharmacology*,  therapeutic use
Pyrazines / adverse effects,  pharmacology*,  therapeutic use
Survival Analysis
T-Lymphocytes, Cytotoxic / cytology,  drug effects,  immunology
Transplantation, Homologous
Grant Support
ID/Acronym/Agency:
2 R37 HL56067/HL/NHLBI NIH HHS; N01-CO-12400/CO/NCI NIH HHS; R01 AI 34495/AI/NIAID NIH HHS; R01 CA102282/CA/NCI NIH HHS; R01 CA72669/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Boronic Acids; 0/NF-kappa B; 0/Protease Inhibitors; 0/Pyrazines; 0/bortezomib
Comments/Corrections
Erratum In:
Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12777

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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