Document Detail


Bis(pivaloyloxymethyl) thymidine 5'-phosphate is a cell membrane-permeable precursor of thymidine 5'-phosphate in thymidine kinase deficient CCRF CEM cells.
MedLine Citation:
PMID:  15826601     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Bis(pivaloyloxymethyl) thymidine 5-phosphate (POM(2)-dTMP) has been investigated as a membrane-permeable prodrugs of dTMP. The growth inhibitory activity of POM(2)-TMP has been compared with thymidine (TdR) in wild type CCRF CEM cells (CEM) and a strain that lacks TdR kinase (CEM tk-). After 72 h incubation at 37 degrees C, TdR showed significant antiproliferative activity (IC(50)=27 microM) against CEM cells but was weakly effective (IC(50)=730 microM) against the mutant cell line. By comparison, bis(pivaloyloxymethyl) thymidine 5'-monophosphate (POM(2)-dTMP) was equally inhibitory (IC(50)=5 microM) to both cell lines. The growth inhibitory effects were reversed by deoxycytidine. Cellular [methyl-(3)H]dTTP pools increased linearly over 2h during incubation of CEM or CEM tk- with 5 microM POM(2)-[methyl-(3)H]dTMP. The incorporation of [methyl-(3)H]TdR into HClO(4)-insoluble cell residue by CEM tk- was <0.1% that of CEM and did not increase over 1h. In contrast, CEM tk- incorporated radioactivity from POM(2)-dTMP into acid insoluble residue at a rate 59% that of CEM. These results demonstrate that POM(2)-dTMP can penetrate into cells and serve as a source of dTMP.
Authors:
Saeed R Khan; Billie Nowak; William Plunkett; David Farquhar
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  69     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-04-13     Completed Date:  2005-05-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1307-13     Citation Subset:  IM    
Affiliation:
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. khansa@jhmi.edu
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MeSH Terms
Descriptor/Qualifier:
Carbon Radioisotopes
Cell Line, Tumor
Cell Proliferation / drug effects
Deoxycytidine / metabolism,  pharmacology
Dose-Response Relationship, Drug
Humans
Inhibitory Concentration 50
Kinetics
Nuclear Magnetic Resonance, Biomolecular
Permeability
Prodrugs / metabolism*
T-Lymphocytes / metabolism*
Thymidine / pharmacology
Thymidine Kinase / deficiency*,  metabolism
Thymidine Monophosphate / metabolism*,  pharmacology*
Grant Support
ID/Acronym/Agency:
CA 16672/CA/NCI NIH HHS; CA 80386/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Carbon Radioisotopes; 0/Prodrugs; 365-07-1/Thymidine Monophosphate; 50-89-5/Thymidine; 951-77-9/Deoxycytidine; EC 2.7.1.21/Thymidine Kinase

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


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