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NF-kappaB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145. Blood 2006 Jan 15;107(2):827-34 PMID: 16174760 PMCID: PMC1895627

Pubmed ID

16174760

Abstract

NF-kappaB is a transcription factor that controls the expression of a number of genes important for mediating immune and inflammatory responses. In this study, we examined whether bortezomib and PS-1145, each of which inhibits NF-kappaB, could protect mice from lethal graft-versus-host disease (GVHD), which is characterized by immune activation and proinflammatory cytokine production. When administered within the first 2 days after transplantation, bortezomib and PS-1145 both protected mice from fatal GVHD, did not compromise donor engraftment, and effected marked reduction in the levels of serum cytokines that are normally increased during GVHD. Extending the course of bortezomib administration or delaying the initiation of this agent for as few as 3 days after bone marrow transplantation (BMT), however, significantly exacerbated GVHD-dependent mortality because of severe pathological damage in the colon. In contrast, prolonged administration of PS-1145, which, unlike bortezomib, is a selective inhibitor of NF-kappaB, caused no early toxicity and resulted in more complete protection than that observed with an abbreviated PS-1145 treatment schedule. These results confirm a critical role for NF-kappaB in the pathophysiology of GVHD and indicate that targeted inhibition of NF-kappaB may have a superior therapeutic index and may constitute a viable therapeutic approach to reduce GVHD severity.

Author List

Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR

Authors

William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin
Parameswaran Hari MD Chief, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Bone Marrow Transplantation
Boronic Acids
Bortezomib
Colon
Cytokines
Graft Survival
Graft vs Host Disease
H-2 Antigens
Heterocyclic Compounds, 3-Ring
Leukocyte Common Antigens
Mice
Mice, Knockout
NF-kappa B
Pyrazines
Pyridines
Survival Rate
jenkins-FCD Prod-321 98992d628744e349846c2f62ac68f241d7e1ea70