3'-Azido-2',3'-dideoxythymidine induced deficiency of thymidine kinases 1, 2 and deoxycytidine kinase in H9 T-lymphoid cells. 2002

Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
Department of Hematology & Oncology, Institute of Medical Virology, JWG University Frankfurt/M., Paul-Ehrlich Strasse 40, 60596 Frankfurt/M., Germany.

Continuous cultivation of T-lymphoid H9 cells in the presence of 3'-azido-2',3'-dideoxythymidine (AZT) resulted in a cell variant cross-resistant to both thymidine and deoxycytidine analogs. Cytotoxic effects of AZT, 2',3'-didehydro-3'-deoxythymidine as well as different deoxycytidine analogs such as 2',3'-dideoxycytidine, 2',2'-difluoro-2'-deoxycytidine (dFdC) and 1-ss-D-arabinofuranosylcytosine (Ara-C) were strongly reduced in H9 cells continuously exposed to AZT when compared to parental cells (>8.3-, >6.6-, >9.1-, 5 x 10(4)-, 5 x 10(3)-fold, respectively). Moreover, anti-HIV-1 effects of AZT, d4T, ddC and 2',3'-dideoxy-3'-thiacytidine (3TC) were significantly diminished (>222-, >25-, >400-, >200-fold, respectively) in AZT-resistant H9 cells. Study of cellular mechanisms responsible for cross-resistance to pyrimidine analogs in AZT-resistant H9 cells revealed decreased mRNA levels of thymidine kinase 1 (TK1) and lack of deoxycytidine kinase (dCK) mRNA expression. The loss of dCK gene expression was confirmed by western blot analysis of dCK protein as well as dCK enzyme activity assay. Moreover, enzyme activity of TK1 and TK2 was reduced in AZT-resistant cells. In order to determine whether lack of dCK affected the formation of the active triphosphate of the deoxycytidine analog dFdC, dFdCTP accumulation and retention was measured in H9 parental and AZT-resistant cells after exposure to 1 and 10 microM dFdC. Parental H9 cells accumulated about 30 and 100 pmol dFdCTP/10(6) cells after 4hr, whereas in AZT-resistant cells no dFdCTP accumulation was detected. These results demonstrate that continuous treatment of H9 cells in the presence of AZT selected for a thymidine analog resistant cell variant with cross-resistance to deoxycytidine analogs, due to deficiency in TK1, TK2, and dCK.

UI MeSH Term Description Entries
D003570 Cytidine Triphosphate Cytidine 5'-(tetrahydrogen triphosphate). A cytosine nucleotide containing three phosphate groups esterified to the sugar moiety. CTP,CRPPP,Magnesium CTP,Mg CTP,Triphosphate, Cytidine
D003841 Deoxycytidine A nucleoside component of DNA composed of CYTOSINE and DEOXYRIBOSE. Cytosine Deoxyribonucleoside,Cytosine Deoxyriboside,Deoxyribonucleoside, Cytosine,Deoxyriboside, Cytosine
D003842 Deoxycytidine Kinase An enzyme that catalyzes reversibly the phosphorylation of deoxycytidine with the formation of a nucleoside diphosphate and deoxycytidine monophosphate. Cytosine arabinoside can also act as an acceptor. All natural nucleoside triphosphates, except deoxycytidine triphosphate, can act as donors. The enzyme is induced by some viruses, particularly the herpes simplex virus (HERPESVIRUS HOMINIS). EC 2.7.1.74. Kinase, Deoxycytidine
D004352 Drug Resistance, Microbial The ability of microorganisms, especially bacteria, to resist or to become tolerant to chemotherapeutic agents, antimicrobial agents, or antibiotics. This resistance may be acquired through gene mutation or foreign DNA in transmissible plasmids (R FACTORS). Antibiotic Resistance,Antibiotic Resistance, Microbial,Antimicrobial Resistance, Drug,Antimicrobial Drug Resistance,Antimicrobial Drug Resistances,Antimicrobial Resistances, Drug,Drug Antimicrobial Resistance,Drug Antimicrobial Resistances,Drug Resistances, Microbial,Resistance, Antibiotic,Resistance, Drug Antimicrobial,Resistances, Drug Antimicrobial
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000093542 Gemcitabine A deoxycytidine antimetabolite used as an antineoplastic agent. 2',2'-Difluoro-2'-Deoxycytidine,2',2'-Difluorodeoxycytidine,2'-Deoxy-2',2''-Difluorocytidine-5'-O-Monophosphate,2'-Deoxy-2'-Difluorocytidine,Gemcitabine Hydrochloride,Gemcitabine, (D-threo-pentafuranosyl)-Isomer,Gemcitabine, (alpha-D-threo-pentofuranosyl)-Isomer,Gemcitabine, (beta-D-threo-pentafuranosyl)-Isomer,Gemicitabine,2',2'-DFDC,Gemzar,LY 188011,LY-188011,dFdCyd,188011, LY,2' Deoxy 2' Difluorocytidine,2' Deoxy 2',2'' Difluorocytidine 5' O Monophosphate,Hydrochloride, Gemcitabine
D000255 Adenosine Triphosphate An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
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

Related Publications

Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
August 1997, Antiviral research,
Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
January 2004, Life sciences,
Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
June 2003, International journal of molecular medicine,
Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
January 2006, Antiviral therapy,
Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
May 2000, International journal of pharmaceutics,
Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
December 1999, Molecular pharmacology,
Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
August 2004, Antiviral research,
Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
May 2017, Annals of neurology,
Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
September 1998, The Journal of pharmacy and pharmacology,
Bettina Gröschel, and Andreas Kaufmann, and Gerold Höver, and Jaroslav Cinatl, and Hans Wilhelm Doerr, and Paul Noordhuis, and Willem J P Loves, and Godefridus J Peters, and Jindrich Cinatl
January 1991, Advances in experimental medicine and biology,
Copied contents to your clipboard!