Document Detail

Evaluation of a UCMK/dCK fusion enzyme for gemcitabine-mediated cytotoxicity.
MedLine Citation:
PMID:  22093835     Owner:  NLM     Status:  MEDLINE    
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.
Adam J Johnson; Melissa N Brown; Margaret E Black
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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.
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MeSH Terms
Antimetabolites, Antineoplastic / pharmacology*
CHO Cells
Deoxycytidine / analogs & derivatives*,  pharmacology
Deoxycytidine Kinase / genetics,  metabolism*
Drug Resistance, Neoplasm*
Nucleoside-Phosphate Kinase / genetics,  metabolism*
Protein Engineering
Recombinant Fusion Proteins / genetics,  metabolism*
Grant Support
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
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Recombinant Fusion Proteins; 0W860991D6/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC Kinase; EC kinase; EC Kinase

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

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