title: Bis(pivaloyloxymethyl) thymidine 5'-phosphate is a cell membrane-permeable precursor of thymidine 5'-phosphate in thymidine kinase deficient CCRF CEM cells.
abstract: 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.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. khansa@jhmi.edu
authors.forename: Saeed R
authors.initials: SR
authors.lastname: Khan
authors.forename: Billie
authors.initials: B
authors.lastname: Nowak
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: David
authors.initials: D
authors.lastname: Farquhar
mesh_terms: D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D010539:Permeability; D011355:Prodrugs / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D013936:Thymidine / Q000494:pharmacology; D013937:Thymidine Kinase / Q000172:deficiency* / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D002250:Carbon Radioisotopes; D011355:Prodrugs; D003841:Deoxycytidine; D013938:Thymidine Monophosphate; D013937:Thymidine Kinase; D013936:Thymidine