Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the 5 years since its release for clinical use, acyclovir (9-[2-hydroxyethoxymethyl]guanine) has proved to be a safe and effective agent for therapy of herpes simplex and varicella-zoster infections. The drug's availability in topical, oral, and intravenous preparations has allowed its use in a range of clinical situations. Acyclovir must be phosphorylated by viral thymidine kinase in infected cells, where it then acts to inhibit viral DNA replication specifically. Epstein-Barr virus and human cytomegalovirus infections do not seem to respond to acyclovir therapy, although in-vitro effects on these viruses may be seen. Acyclovir is well absorbed and distributed, with cerebrospinal fluid levels 50% that of plasma. Clearance is almost entirely by the renal route, with a half-life of 20 hours in the anuric patient. Acyclovir has an excellent safety profile, its major adverse effect being transient serum creatinine elevations during high-dose intravenous use. Major uses include treatment of primary and recurrent genital herpes and herpes encephalitis and prophyllaxis and therapy of mucocutaneous herpes and varicella-zoster infections in immunocompromised patients. Resistance to acyclovir in herpes simplex virus is rarely encountered and does not seem to be due to long-term chronic suppressive therapy.
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PMID:Drugs five years later: acyclovir. 331 10

A survey is given on 23 patients (10 of our own, 13 reported in personal communications and in the literature) suffering from lymphoproliferative diseases and treated with acyclovir (ACV). In 5 patients (3 of 18 with cutaneous T-cell lymphomas, 2 of 5 with lymphomatoid papulosis) partial remission could be achieved. Since herpes simplex virus, cytomegalovirus and viruses like Epstein-Barr and varicella-zoster do not play an etiologic role and since HTLV-I virus, due to its lack of thymidine kinase, cannot activate ACV, the following mechanisms should be discussed regarding the possible effectiveness of ACV in lymphoproliferative diseases: a direct cytopathic effect; activation of ACV by the thymidine kinase of viruses not yet detected in cutaneous lymphoproliferative disorders; ACV activation by cellular thymidine kinase, which has been found to be elevated in lymphoproliferative disorders. Preliminary clinical observations suggest that ACV may exhibit an antiproliferative effect intravenously in some patients with lymphomatoid papulosis.
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PMID:[Acyclovir in mycosis fungoides and lymphomatoid papulosis]. 353 73

Bromovinyldeoxyuridine (BVDU) is a highly potent and selective antiherpetic agent which offers great potential for the treatment of severe herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections in cancer patients. BVDU inhibits the replication of HSV-1 and VZV at a concentration as low as 1-10 ng/ml; and the proliferation of tumor cells transformed with the HSV-1 thymidine kinase gene is even inhibited by BVDU concentrations lower than 1 ng/ml. Moreover, BVDU is inhibitory to Epstein-Barr virus replication in vitro at a concentration of 0.02 micrograms/ml. Due to the action of pyrimidine nucleoside phosphorylases, BVDU is rapidly degraded to the free pyrimidine base bromovinyluracil (BVU). In contrast to BVDU, which is cleared from the bloodstream within 2-3 hours, BVU persists in the plasma for at least 24 hours. During this period BVU can be converted again to BVDU upon administration of deoxythymidine, deoxyuridine or any other deoxyribonucleoside capable of transferring its deoxyribosyl moiety onto BVU. BVU owes its long persistence in the bloodstream to the fact that it does not act as substrate for dihydrothymine dehydrogenase, the enzyme that catalyzes the first step in the catabolic pathway of pyrimidines. On the contrary, BVU acts as an efficient inhibitor of this enzyme and thereby prevents the degradation of fluorouracil (FU), a well-known anticancer agent. As a consequence, BVDU via BVU enhances the antitumor activity of FU, as has been demonstrated in the murine P388 leukemia model. Thus, BVDU may be useful in anticancer chemotherapy from several viewpoints, e.g. for treatment of intercurrent herpesvirus infections, and, in combination with FU, for treatment of those malignant diseases that are amenable to FU therapy.
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PMID:Potential of bromovinyldeoxyuridine in anticancer chemotherapy. 375 35

The P3HR-1 line of human lymphoblastoid cells that is Epstein-Barr virus positive was made resistant to 5-bromodeoxyuridine. Epstein-Barr virus-associated antigens, but not virus particles, were produced in P3HR-1(BU) cells maintained on 5-bromodeoxyuridine. However, virus particles did appear within 4 days after removal of the drug. Thymidine kinase activity was limited to P3HR-1(BU) cells producing viral antigen, whereas all control P3HR-1 cells showed thymidine kinase activity regardless of viral antigen synthesis. Cellular DNA in most P3HR-1(BU) cells was made via pathways that did not involve thymidine kinase. In cells having a pathway that involved thymidine kinase, a second DNA of density 1.71 g/cm(3), corresponding to Epstein-Barr virus, was detected.IT WAS CONCLUDED THAT: (a) a repressed Epstein-Barr virus genome persists in P3HR-1(BU) cells that do not contain thymidine kinase, with activation of the viral genome being accompanied by productive infection and the appearance of enzyme, and (b) thymidine kinase activity in P3HR-1(BU) cells could be used as a marker for viral genome expression.
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PMID:Persistence of a repressed Epstein-Barr virus genome in Burkitt lymphoma cells made resistant to 5-bromodeoxyuridine. 433 12

The sequence of spontaneous Epstein-Barr virus activation was studied in P3HR-1 carrier cells and in P3HR-1(BrdU) cells made resistant to 5-bromodeoxyuridine. Virus activation was initiated during the normal cell cycle, and recruitment of additional virus-activated cells was prevented by the DNA inhibitors, 1-beta-D-arabinofuranosylcytosine and hydroxyurea. Virus activation was followed by synthesis of the early antigen complex in the absence of additional detectable DNA synthesis. Early antigen synthesis was followed by hydroxyurea-resistant synthesis of new DNA, which in the case of P3HR-1(BrdU) cells was characterized by the appearance of thymidine kinase. The newly synthesized DNA banded in neutral cesium chloride at peaks corresponding to normal human DNA and Epstein-Barr viral DNA. Synthesis of viral antigen was seen only in cells that had undergone hydroxyurea-resistant DNA synthesis.
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PMID:Sequence of spontaneous Epstein-Barr virus activation and selective DNA synthesis in activated cells in the presence of hydroxyurea. 434

Gene expression of Epstein-Barr virus (EBV) was studied after microinjection of viral DNA into different types of cells. Raji TK- cells, known to express viral gene functions after superinfection with the EBV-P3HR-1 virus strain, were attached to plastic dishes by using anti-lymphocyte IgG, phytohemagglutinin, or concanavalin A as a ligand. It was difficult to inject DNA into the small and fragile Raji cells. After formation of polykaryons by cell fusion, microinjection became more efficient. At 24 hr after injection of P3HR-1 virus DNA, 90-100% of the injected cells expressed the early antigen complex as observed by immunofluorescence staining; 70-80% of the cells simultaneously incorported [3H]thymidine, indicating that thymidine kinase is expressed after injection of viral DNA. Additionally, synthesis of the virus capsid antigen was demonstrated in 20-30% of the recipient Raji cells. Human diploid fibroblasts, African green monkey kidney cells, and rat fibroblasts, which do not represent natural target cells for EBV, could also be induced to synthesis of early antigen complex by injection of P3HR-1 virus DNA.
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PMID:Expression of Epstein-Barr virus genes in different cell types after microinjection of viral DNA. 624 58

The activities throughout the cell cycle of thymidine kinase (EC 2.7.1.21), dihydrothymine dehydrogenase (EC 1.3.1.2), thymidine phosphorylase (EC 2.4.2.4) and dTMP phosphatase (EC 3.3.3.35) were measured in the Epstein-Barr virally transformed human B lymphocyte line LAZ-007. Cells were synchronised at different stages of the cell cycle using the technique of centrifugal elutriation. The degree of synchrony in each cycle-stage cell population was determined by flow microfluorimetric analysis of DNA content and by measurement of thymidine incorporation into DNA. The activity of the anabolic enzyme thymidine kinase was low in the G1 phase cells, but increased manyfold during the S and G2 phases, reaching a maximum after the peak of DNA synthesis, then decreasing in late G2 + M phase. By contrast, the specific activities of the enzymes involved in thymidine and thymidylate catabolism, dihydrothymine dehydrogenase, thymidine phosphorylase and dTMP phosphatase remained essentially constant throughout the cell cycle, indicating that the fate of thymidine at different stages of the cell cycle is governed primarily by regulation of the level of the anabolic enzyme thymidine kinase and not by regulation of the levels of thymidine catabolising enzymes.
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PMID:The activities of thymidine metabolising enzymes during the cell cycle of a human lymphocyte cell line LAZ-007 synchronised by centrifugal elutriation. 626 Jan 57

The Epstein Barr nuclear antigen (EBNA) and the rheumatoid arthritis nuclear antigen (RANA) develop in human B lymphocytes that have been infected and transformed by Epstein Barr virus (EBV). Antibodies to RANA and EBNA are found only in individuals with prior exposure to EBV. The purpose of the present studies was to determine the relation of the 2 antigens to each other and to EBV genetic material, in human-rodent somatic cell hybrids. Cultured human B lymphoblastoid cells, Raji, Daudi, and RPMI 4098 were fused with thymidine kinase-deficient mouse or hamster fibroblasts. After selection and cloning in ouabain-HAT medium, the hybrid nature of the surviving cells was confirmed by isozyme analysis. The hybrid clones were analyzed for EBNA by anti-complement im,munofluorescence, and for RANA by anti-immunoglobulin immunofluorescence and immunodiffusion. The results showed that RANA and EBNA segregated entirely independently of each other in the hybrid clones. Two methods were used to detect the presence of EBV DNA sequences in the intracellular DNA of hybrid clones. The 1st method relied on the hybridization of labeled cRNA prepared from virion DNA with DNA from 8 hybrid clones affixed to nitrocellulose filters. The 2nd approach was to hybridize labeled intracellular DNA from 3 hybrid clones to Southern blots of cloned fragments of EBV DNA. These results suggested that the presence of EBV DNA was not sufficient for the expression of either antigen. One stable RANA-positive hybrid cell line contained at least 80% of the EBV genome in the absence of detectable EBNA.
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PMID:Discordant expression of 2 Epstein-Barr virus-associated antigens, EBNA and RANA, in man-rodent somatic cell hybrids. 626 53

Epstein-Barr virus (EBV) from P3HR-1 cells, but not from B95-8 cells, can induce the synthesis of thymidine kinase (TK) in TK-negative Raji cells. The synthesis of TK was slightly reduced, but not inhibited, when cells were cultivated in the presence of cytosine arabinoside (ara-C). On the other hand, the synthesis of TK in ordinary Raji cells was enhanced in the presence of the drug. Thymidine-beta-D-arabinofuranoside (ara-T) was capable of reducing the conversion rate of thymidine to TdR nucleotides by extracts prepared from superinfected Raji TK-cells, but had no influence on TK activity in cell extracts from ordinary Raji cells and EBV-negative Ramos cells. This suggested a broader substrate specificity of the virally induced enzyme.
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PMID:Synthesis of thymidine kinase (TK) in Epstein-Barr virus-superinfected Raji TK-negative cells. 626 68

A virus-specified thymidine kinase appears to be a general requirement for herpes virus susceptibility to the antiviral effect of acyclovir. Surprisingly, mouse cytomegalovirus (MCMV), which does not encode for a thymidine kinase, is exquisitely sensitive to the drug both in vitro and in vivo. The drug is active against the virus in the absence of a cellular thymidine kinase and the antiviral activity is not diminished in the presence of excess thymidine or a variety of nucleosides and deoxynucleosides. Thus, a thymidine phosphorylation pathway is not required for the drug's activation of this infection. The enzyme system responsible for phosphorylation of the drug has not been identified. Mouse cytomegalovirus mutants resistant to the drug have been isolated, indicating that the antiMCMV effect results from selective inhibition of viral replication rather than indirectly through toxicity to the host cell. Eight resistant mutants appear to be in the same complementation group and seven of the mutants demonstrate coresistance to phosphonoacetic acid, a marker for the DNA polymerase locus of herpes viruses. The evidence to date indicates that the MCMV DNA polymerases is the final site of action of the drug. Investigations of the antiMCMV activity of acyclovir should provide insights into the antiviral effects of this drug and other nucleoside analogs in other herpes virus infections in which the virus does not code for a thymidine kinase (for example, human cytomegalovirus and Epstein-Barr virus).
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PMID:Acyclovir in mouse cytomegalovirus infections. 628 1


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