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Metabolism and activities of 3'-azido-2',3'-dideoxythymidine and 2',3'-didehydro-2',3'-dideoxythymidine in herpesvirus thymidine kinase transduced T-lymphocytes. 1997

R R Drake, and R McMasters, and S Krisa, and S D Hume, and T M Rechtin, and R L Saylors, and Y Chiang, and R Govindarajan, and N C Munshi
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.

T-lymphocytes transduced with the conditionally toxic herpesvirus thymidine kinase gene (HSV-1 TK) are increasingly becoming important tools in genetic therapy approaches for treating viral infections and cancers. Therefore, the effects of different antiviral nucleoside drugs on the growth inhibition of parental and HSV-1 TK-transduced human T-lymphocyte cell lines (H9 and CEM TK-) were examined. As expected, both transduced cell lines were most sensitive to growth inhibition by ganciclovir (GCV). While the presence of HSV-1 TK did not potentiate 3'-azido-2',3'-dideoxythymidine (AZT) growth inhibition of H9 cells containing cellular TK; transduction of HSV-1 TK into the cellular TK-deficient CEM cells (CEM TK-) restored sensitivity to AZT. In both transduced cell lines, an HSV-1 TK-dependent growth inhibition with 2',3'-didehydro-2',3'-dideoxythymidine (d4T) was observed and a Km of 143 microM for d4T and HSV-1 TK was determined. Metabolic labeling analysis showed that drug metabolism correlated with the observed effects on cell growth. The effects of HIV-1 replication in the CEM TK- cell lines in the presence of AZT or d4T was evaluated. CEM TK- cells are largely resistant to AZT or d4T inhibition of HIV-1 replication, however, transduction of HSV-1 TK into the CEM TK- cells completely restored AZT and d4T inhibition of HIV-1 replication. These studies confirm the requirement for a thymidine kinase activity for the anti-HIV activities of d4T and suggest that AZT, but not d4T, could be potentially administered to patients receiving HSV-1 TK-transduced lymphocytes.

UI MeSH Term Description Entries
D009705 Nucleosides Purine or pyrimidine bases attached to a ribose or deoxyribose. (From King & Stansfield, A Dictionary of Genetics, 4th ed) Nucleoside,Nucleoside Analog,Nucleoside Analogs,Analog, Nucleoside,Analogs, Nucleoside
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006131 Growth Inhibitors Endogenous or exogenous substances which inhibit the normal growth of human and animal cells or micro-organisms, as distinguished from those affecting plant growth ( Cell Growth Inhibitor,Cell Growth Inhibitors,Growth Inhibitor,Growth Inhibitor, Cell,Growth Inhibitors, Cell,Inhibitor, Cell Growth,Inhibitor, Growth,Inhibitors, Cell Growth,Inhibitors, Growth
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006918 Hydroxyurea An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. Hydroxycarbamid,Hydrea,Oncocarbide
D000212 Acyclovir A GUANOSINE analog that acts as an antimetabolite. Viruses are especially susceptible. Used especially against herpes. Acycloguanosine,9-((2-Hydroxyethoxy)methyl)guanine,Aci-Sanorania,Acic,Aciclobeta,Aciclostad,Aciclovir,Aciclovir Alonga,Aciclovir-Sanorania,Acifur,Acipen Solutab,Acivir,Activir,Acyclo-V,Acyclovir Sodium,Antiherpes Creme,Avirax,Cicloferon,Clonorax,Cusiviral,Genvir,Herpetad,Herpofug,Herpotern,Herpoviric,Isavir,Laciken,Mapox,Maynar,Milavir,Opthavir,Supraviran,Viclovir,Vipral,Virax-Puren,Virherpes,Virmen,Virolex,Virupos,Virzin,Wellcome-248U,Zoliparin,Zovirax,Zyclir,aciclovir von ct,Aci Sanorania,Aciclovir Sanorania,Acyclo V,Alonga, Aciclovir,Sodium, Acyclovir,Solutab, Acipen,Virax Puren,ViraxPuren,Wellcome 248U,Wellcome248U
D013379 Substrate Specificity A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. Specificities, Substrate,Specificity, Substrate,Substrate Specificities
D013601 T-Lymphocytes Lymphocytes responsible for cell-mediated immunity. Two types have been identified - cytotoxic (T-LYMPHOCYTES, CYTOTOXIC) and helper T-lymphocytes (T-LYMPHOCYTES, HELPER-INDUCER). They are formed when lymphocytes circulate through the THYMUS GLAND and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T Cell,T Lymphocyte,T-Cells,Thymus-Dependent Lymphocytes,Cell, T,Cells, T,Lymphocyte, T,Lymphocyte, Thymus-Dependent,Lymphocytes, T,Lymphocytes, Thymus-Dependent,T Cells,T Lymphocytes,T-Cell,T-Lymphocyte,Thymus Dependent Lymphocytes,Thymus-Dependent Lymphocyte
D013937 Thymidine Kinase An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. Deoxythymidine Kinase,Deoxypyrimidine Kinase,Kinase, Deoxypyrimidine,Kinase, Deoxythymidine,Kinase, Thymidine

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