Document Detail

The role of nucleoside/nucleotide transport and metabolism in the uptake and retention of 3'-fluoro-3'-deoxythymidine in human B-lymphoblast cells.
MedLine Citation:
PMID:  21982569     Owner:  NLM     Status:  MEDLINE    
INTRODUCTION: Recent studies in the human adenocarcinoma cell line A549 have identified cell growth-dependent equilibrative nucleoside transporter-1 (hENT1) as a modifier of 3'-fluoro-3'-deoxythymidine (FLT) uptake and retention. In the present study, we used the ability to isolate human lymphoblastoid clones deficient in thymidine kinase 1 (TK1) to study how metabolism and nucleoside transport influence FLT uptake and retention.
METHODS: Transport and metabolism of FLT were measured in the human lymphoblastoid cell line TK6 and in eight clones isolated from TK6. Four clones were TK1-proficient, while four were TK1-deficient. Both influx and efflux of FLT were measured under conditions where concentrative and equilibrative transport could be distinguished.
RESULTS: Sodium-dependent concentrative FLT transport dominated over equilibrative transport mechanisms and while inhibition of hENT1 reduced FLT uptake, there were no correlations between clonal variations in hENT1 levels and FLT uptake. There was an absolute requirement of TK1 for concentration of FLT in TK6 cells. FLT uptake reached a peak after 60 min of incubation with FLT after which intracellular levels of FLT and FLT metabolites declined. Efflux was rapid and was associated with reductions in FLT and each of its metabolites. Both FLT and FLT-monophosphate were found in the efflux buffer.
CONCLUSIONS: Initial rates of FLT uptake were a function of both concentrative and equilibrative transporters. TK1 activity was an absolute requirement for the accumulation of FLT. Retention was dependent on nucleoside/nucleotide efflux and retrograde metabolism of FLT nucleotides.
David A Plotnik; Lena J McLaughlin; Jenny Chan; Joshua N Redmayne-Titley; Jeffrey L Schwartz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-06-22
Journal Detail:
Title:  Nuclear medicine and biology     Volume:  38     ISSN:  1872-9614     ISO Abbreviation:  Nucl. Med. Biol.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-10     Completed Date:  2012-02-03     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  9304420     Medline TA:  Nucl Med Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  979-86     Citation Subset:  IM    
Copyright Information:
Published by Elsevier Inc.
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MeSH Terms
Biological Transport
Cell Line
Cell Proliferation
Dideoxynucleosides / metabolism*
Equilibrative Nucleoside Transporter 1 / metabolism
Lymphocytes / cytology,  enzymology,  metabolism*
Nucleotides / metabolism*
Sodium / metabolism
Thymidine Kinase / deficiency,  metabolism
Grant Support
CA118130/CA/NCI NIH HHS; R01 CA118130/CA/NCI NIH HHS; R01 CA118130-03/CA/NCI NIH HHS
Reg. No./Substance:
0/Dideoxynucleosides; 0/Equilibrative Nucleoside Transporter 1; 0/Nucleotides; 0/SLC29A1 protein, human; 9NEZ333N27/Sodium; EC Kinase; EC kinase 1; PG53R0DWDQ/alovudine

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