Document Detail


Synthetic lethality for linking the mycophenolate mofetil mode of action with molecular disease and drug profiles.
MedLine Citation:
PMID:  23014771     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Systematic study of the effect of mycophenolate mofetil (MMF) on the molecular level in the context of other drugs and molecular disease profiles became possible due to the availability of large scale molecular profiles on both disease characterization and drug mode of action. Such analysis is of particular value in elucidating alternative drug use for addressing clinically unmet needs, and the concept of synthetic lethality provides an alternative tool for such repositioning strategies. Resting on consolidation of transcriptomics data and literature mining, a MMF molecular footprint became available including a set of 170 genes specifically affected by the drug. Analysis of this profile on a molecular pathway level reveals a set of 14 pathways as affected. Next to assignment of molecular pathways and associated diseases synergistic drug combinations are proposed by utilizing the synthetic lethal interaction network. Of particular interest is the combination of MMF with adenosine deaminase inhibitors, sulfasalazine, and other selected drugs interfering with calcium-based regulatory pathways and metabolism. Indeed analysis of drugs in clinical trials positively identifies combinations with MMF in the context of synthetic lethality and affected pathways, particularly in diseases such as multiple sclerosis, vasculitis, GVHD and lupus nephritis. Importantly, the synthetic lethal interaction of the drug mode of action is an interesting basis for rational repositioning strategies by suggesting combinations which exhibit a synergistic rather than a mere additive effect, as for example is evident for the combination of tacrolimus and MMF. Inherent is also the assessment of possible adverse effects of drug combinations.
Authors:
Johannes Söllner; Paul Mayer; Andreas Heinzel; Raul Fechete; Christian Siehs; Rainer Oberbauer; Bernd Mayer
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular bioSystems     Volume:  8     ISSN:  1742-2051     ISO Abbreviation:  Mol Biosyst     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-30     Completed Date:  2013-05-02     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101251620     Medline TA:  Mol Biosyst     Country:  England    
Other Details:
Languages:  eng     Pagination:  3197-207     Citation Subset:  IM    
Affiliation:
Emergentec Biodevelopment GmbH, 1180 Wien, Austria. johannes.soellner@emergentec.com
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adenosine Deaminase Inhibitors / pharmacology
Calcium / metabolism
Drug Combinations
Drug Interactions*
Drug Synergism
Drug Therapy, Combination*
Humans
Immunosuppressive Agents / pharmacology
Metabolic Networks and Pathways / drug effects
Mycophenolic Acid / adverse effects,  analogs & derivatives*,  pharmacology
Sulfasalazine / pharmacology
Tacrolimus / pharmacology
Chemical
Reg. No./Substance:
0/Adenosine Deaminase Inhibitors; 0/Drug Combinations; 0/Immunosuppressive Agents; 109581-93-3/Tacrolimus; 24280-93-1/Mycophenolic Acid; 599-79-1/Sulfasalazine; 7440-70-2/Calcium; 9242ECW6R0/mycophenolate mofetil

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


Previous Document:  Clinical review: Biomarkers of acute kidney injury: where are we now?
Next Document:  A Validated Spectrofluorimetric Method for the Determination of Citalopram in Bulk and Pharmaceutica...