| Bis(pivaloyloxymethyl) thymidine 5'-phosphate is a cell membrane-permeable precursor of thymidine 5'-phosphate in thymidine kinase deficient CCRF CEM cells. | |
MedLine Citation:
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PMID: 15826601 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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:
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Saeed R Khan; Billie Nowak; William Plunkett; David Farquhar |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Biochemical pharmacology Volume: 69 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2005 May |
Date Detail:
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Created Date: 2005-04-13 Completed Date: 2005-05-24 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1307-13 Citation Subset: IM |
Affiliation:
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The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. khansa@jhmi.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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CA 16672/CA/NCI NIH HHS; CA 80386/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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