| Evaluation of a UCMK/dCK fusion enzyme for gemcitabine-mediated cytotoxicity. | |
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MedLine Citation:
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PMID: 22093835 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Adam J Johnson; Melissa N Brown; Margaret E Black |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-11-10 |
Journal Detail:
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Title: Biochemical and biophysical research communications Volume: 416 ISSN: 1090-2104 ISO Abbreviation: Biochem. Biophys. Res. Commun. Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-13 Completed Date: 2012-01-27 Revised Date: 2013-02-19 |
Medline Journal Info:
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Nlm Unique ID: 0372516 Medline TA: Biochem Biophys Res Commun Country: United States |
Other Details:
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Languages: eng Pagination: 199-204 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
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School of Molecular Biosciences, College of Veterinary Medicine, P.O. Box 647520, Washington State University, Pullman, WA 99164-7520, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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:
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0/Antimetabolites, Antineoplastic; 0/Recombinant Fusion Proteins; 103882-84-4/gemcitabine; 951-77-9/Deoxycytidine; EC 2.7.1.74/Deoxycytidine Kinase; EC 2.7.4.14/cytidylate kinase; EC 2.7.4.4/Nucleoside-Phosphate Kinase |
| Comments/Corrections | |
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