Document Detail


Evaluation of a UCMK/dCK fusion enzyme for gemcitabine-mediated cytotoxicity.
MedLine Citation:
PMID:  22093835     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
While gemcitabine (2'-2'-difluoro-2'-deoxycytidine, dFdC) displays wide-ranging antineoplastic activity as a single agent, variable response rates and poor intracellular metabolism often limit its clinical efficacy. In an effort to enhance dFdC cytotoxicity and help normalize response rates, we created a bifunctional fusion enzyme that combines the enzymatic activities of deoxycytidine kinase (dCK) and uridine/cytidine monophosphate kinase (UCMK) in a single polypeptide. Our goal was to evaluate whether the created fusion could induce beneficial, functional changes toward dFdC, expedite dFdC conversion to its active antimetabolites and consequently amplify cell dFdC sensitivity. While kinetic analyses revealed the UCMK/dCK fusion enzyme to possess both native activities, the fusion rendered cells sensitive to the cytotoxic effects of dFdC at the same level as dCK expression alone. These results suggest that increased wild-type UCMK expression does not provide a significant enhancement in dFdC-mediated cytotoxicity and may warrant the implementation of studies aimed at engineering UCMK variants with improved activity toward gemcitabine monophosphate.
Authors:
Adam J Johnson; Melissa N Brown; Margaret E Black
Related Documents :
8005615 - Conserved structural features in glycoprotein processing glucosidase i from several tis...
10872205 - Purification and characterization of polygalacturonase from banana fruit.
8896765 - Purification and properties of chitinase from cabbage stems with roots.
8670065 - Biologically active monomeric and heterodimeric recombinant human calpain i produced us...
17896325 - Approach to predict the contribution of cytochrome p450 enzymes to drug metabolism in t...
11472015 - Purification and characterization of an iron-nickel hydrogenase from thermococcus celer.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-11-10
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  416     ISSN:  1090-2104     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-13     Completed Date:  2012-01-27     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  199-204     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Antimetabolites, Antineoplastic / pharmacology*
CHO Cells
Cricetinae
Deoxycytidine / analogs & derivatives*,  pharmacology
Deoxycytidine Kinase / genetics,  metabolism*
Drug Resistance, Neoplasm*
Nucleoside-Phosphate Kinase / genetics,  metabolism*
Protein Engineering
Recombinant Fusion Proteins / genetics,  metabolism*
Transfection
Grant Support
ID/Acronym/Agency:
R01 CA097328/CA/NCI NIH HHS; R01 CA097328-08/CA/NCI NIH HHS; R01CA97328/CA/NCI NIH HHS; T32 GM008336/GM/NIGMS NIH HHS; T32 GM008336-24/GM/NIGMS NIH HHS; T32GM008336/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Recombinant Fusion Proteins; 0W860991D6/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC 2.7.1.74/Deoxycytidine Kinase; EC 2.7.4.14/cytidylate kinase; EC 2.7.4.4/Nucleoside-Phosphate Kinase
Comments/Corrections

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


Previous Document:  miR-125b suppresses the proliferation and migration of osteosarcoma cells through down-regulation of...
Next Document:  A structural model of the HIV-1 Rev-integrase complex: The molecular basis of integrase regulation b...