Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Measurements of the deoxyribonucleoside triphosphate (dNTP) contents, the [14C] thymidine and deoxyuridine incorporation and the "key enzymes" of the thymidine triphosphate (dTTP) synthesis, thymidine kinase and ribonucleotide reductase, in diploid Ehrlich-ascites carcinoma, in Yoshida sarcoma-ascites cells and to a smaller extent in surgically removed malignant human tumours show 1. A distinctly increased dTTP content compared with the remaining dNTP is not a characteristic of tumour cells generally but a peculiarity of sarcoma and a sign of differentiation of a malignant tumour. 2. With simultaneous linear deoxyribonucleoside incorporation the dTTP content and the mix-proportion of [14C] dTTP to total dTTP in ascites tumour cells in short-term in-vitro incubation (120 min) remain constant. 3. Thymidine addition to the medium leads to a distinct rise of dTTP concentration even at a dosage of 3 X 10(-5) M. 4. The dNTP contents of ascites tumour cells are within the range of the endproduct-inhibiting concentrations of thymidine kinase and ribonucleotide reductase.
...
PMID:[Studies on the thymidine-triphosphate synthesis in malignant tumors. I. Effects of thymidine on deoxyribonucleoside triphosphate pools and deoxyribonucleic acid synthesis (author's transl)]. 13 36

A method for producing solid tumors in rat liver or spleen by local inoculation of Yoshida sarcoma or Hirosaki sarcoma was developed by careful selection of rat strains. After development of the tumor, the liver was isolated and perfused with a mixture of calf serum and fluorocarbon. Addition of corticoid hormone to the perfusion fluid induced tyrosine aminotransferase in normal tissue of the liver and to a lesser degree in the tumor tissue. Corticoid did not cause any detectable induction of thymidine kinase in normal tissue of the liver, but caused slight but definite induction of the enzyme in the tumor tissue. Ornithine decarboxylase was induced in the normal tissue by perfusion with serum alone, even without corticoid, but no enzyme induction was observed in the tumor tissue. The low level of this enzyme found in solid tumor tissue might be due to the fact that the enzyme was measured in the late period of tumor growth, because, in experiments with ascites tumor cells, higher enzyme activities were observed in the early period of growth.
...
PMID:Induction of ornithine decarboxylase, tyrosine aminotransferase, and thymidine kinase by glucocorticoid in isolated, perfused liver after tumor inoculation. 24 80

During the fractionation of various enzymes concerned with DNA synthesis from the postmicrosomal supernatant fraction of various tissues, DNA polymerace [EC 2.7.7.7], thymidine kinase [EC 2.7.1.75], dTMP kinase [EC 2.7.4.9], deoxycytidine kinase [EC 2.7.1.74], and deoxycytidine monophosphokinase (dCMP kinase) [EC 2.7.4.14] were found in the pellet fraction of postmicrosomal supernatant. Further, the uridine kinase [EC 2.7.1.48] and aspartate transcarbamylase [EC 2.1.3.2] activities of postmicrosomal supernatant from various tissues were also present in this pellet fraction. The activities of DNA polymerase, thymidine kinase, uridine kinase, and aspartate transcarbamylase from normal and regenerating rat liver, and Yoshida sarcoma were higher in the pellet fraction than in the supernatant. On the other hand, the activities of dTMP kinase, dCMP kinase, and orotidine-5'-phosphate decarboxylase [EC 4.1.1.23] were lower in the pellet fraction than in the supernatant. The pellet fractions of regenerating rat liver and Yoshida sarcoma showed a remarkable incorporation of various precursors (thymidine, dTMP, deoxycytidine, and dCMP) into DNA in the presence of a suitable DNA template, ATP and all four deoxynucleoside 5'-triphosphates for DNA synthesis. Normal adult rat liver catalyzed a much smaller incorporation of all these precursors, except for dCMP.
...
PMID:Intracellular distribution of various enzymes concerned with DNA synthesis from normal and regenerating rat liver, and Yoshida sarcoma. 113 86

The thymidine kinases extracted from the spleen of mice infected with Friend virus and from Yoshida sarcoma in rats were separated into two active peaks by diethylaminoethyl cellulose column chromatography, while those of normal tissues have been found to consist of only the first peak (P-1). The second peak (P-II) was also found in the enzyme from the extract of the spleen when the animals were treated by i.p. injections of 1-acetyl 2-phenylhydrazine. The two P-II peaks from tumor tissue and from spleen enlarged by anemia-inducing agents were indistinguishable on the chromatographic profile. On the other hand, the thymidine kinase extracted with Triton X-100 from a mitochondrial fraction of normal liver was found to consist of only one peak in the same position as the above P-II's on the chromatogram, but its faculty for deoxythymidine triphosphate inhibition was not identical to that of tumor tissue. This treatment with the detergent might cause dissociation of a certain component from the enzyme complex to make the extra peak (P-IIb), but it eventually shifts to P-II on the chromatogram.
...
PMID:Two forms of thymidine kinase in normal and tumor tissues of animals. 127 27

The potential value of retroviral gene transfer as a means of targeting therapeutic genes to neoplastic cells is threatened by the tendency of occasional cells to lose transduced genes or their expression. To determine whether this threat could be reduced by transducing multiple copies of a therapeutic gene, we compared 8 murine sarcoma sublines carrying from 1 to 6 copies of a retrovirally transduced herpes simplex virus thymidine kinase gene, which sensitizes cells to ganciclovir (GCV). When variability consequent to differences in vector integration site was excluded, increased copy number was associated with an increase in GCV sensitivity and a major reduction in the frequency of GCV-resistant mutants. The results suggest a potential means of preserving the efficacy of future antineoplastic gene therapy strategies.
...
PMID:Multiple transduction as a means of preserving ganciclovir chemosensitivity in sarcoma cells carrying retrovirally transduced herpes thymidine kinase genes. 132 36

The ets oncogene superfamily consists of a family of sequence-specific DNA-binding proteins that activate transcription. We have previously identified two new members of the ets oncogene superfamily, namely elk-1 and elk-2. In this report we show that the recombinant elk-1 protein expressed in bacteria, like the c-ets-1 proto-oncogene, binds in a sequence-specific manner to Moloney murine sarcoma virus long terminal repeat, E74 target sequences and the PEA3 motif (polyoma enhancer), but does not bind to PU box sequences. Thus analysis of the DNA-binding specificity of ets-related proteins supports the view that different members show similar DNA-binding specificity, which is a general feature of the homeobox proteins. Our data using the chloramphenicol acetyltransferase gene linked to a thymidine kinase promoter containing multimers of the elk-1 target sequence indicates that elk-1 functions as a transcriptional activator. Interestingly, although elk-1 is the most divergent of all the members of the ets gene family, it shows very close similarities with c-ets-1 in some of its sequence-specific DNA-binding specificities. Here, we propose a new function for the elk-1 gene to act as a transcriptional activator of retroviruses and DNA tumor viruses.
...
PMID:A divergent ets-related protein, elk-1, recognizes similar c-ets-1 proto-oncogene target sequences and acts as a transcriptional activator. 174 Nov 66

Retroviral vectors constructed to contain the herpes simplex virus thymidine kinase (HSV-TK) gene were used for transduction of this gene into murine sarcoma and lymphoma cells to yield sublines susceptible in vitro to the cytotoxicity of ganciclovir, a drug specifically activated by HSV-TK. In vivo, ganciclovir induced complete, durable regressions in most mice bearing transplanted HSV-TK-positive sarcomas; its efficacy against lymphomas was only marginal, possibly because of their greater instability of gene expression. The results imply the potential value of an anticancer strategy entailing the prophylactic use of retroviral vectors to create tissue mosaicism for drug sensitivity.
...
PMID:Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. 229 79

Azidothymidine (AZT, 3'-azido-3'-deoxythymidine, zidovudine) competitively inhibited the activity of thymidine kinase (EC 2.7.1.21) in extracts of rat hepatoma and sarcoma cells; Dixon plots yielded a Ki = 1-2 microM. Azidothymidine (100 microM) exerted synergistic cytotoxicity with methotrexate (0.05 microM) in hepatoma cells in culture in clonogenic assay. Thymidine (50 microM) counteracted the effect of azidothymidine and prevented synergistic action. Azidothymidine (10 microM) was synergistically cytotoxic with 5-fluorouracil (0.3 and 0.5 microM) in HT-29 human colon carcinoma cells. Thymidine (10 microM) abolished synergism. These studies suggest a new role for azidothymidine which, as an inhibitor of thymidine salvage, should enhance synergistically the clinical anticancer impact of blockers of de novo biosynthesis of thymidylates (methotrexate, 5-fluorouracil).
...
PMID:Azidothymidine inhibition of thymidine kinase and synergistic cytotoxicity with methotrexate and 5-fluorouracil in rat hepatoma and human colon cancer cells. 236 52

Bolus doses of 5-chlorodeoxycytidine (CldC) administered with modulators of pyrimidine metabolism, followed by X-irradiation, resulted in a 2-fold dose increase effect against RIF-1 tumors in C3H mice. Pool size studies of the fate of [14C]-CldC in BDF1 mice bearing Sarcoma-180 tumors, which demonstrated the rapid formation of 5-chlorodeoxycytidylate (CldCMP), and incorporation of CldC as such in RIF-1 tumor DNA, indicate that CldC is a substrate for deoxycytidine kinase, as our past Km studies have shown. Our data indicate that 5-chlorodeoxyuridine triphosphate (CldUTP) accumulates from both the cytidine deaminase-thymidine kinase pathway, as well as from the deoxycytidine kinase-dCMP deaminase pathway, in tumor tissue. As shown in a previous study, tetrahydrouridine (H4U), a potent inhibitor of cytidine deaminase, can effectively inhibit the enzyme in the normal tissues of BDF1 mice. When H4U was administered with the modulators N-(phosphonacetyl)-L-aspartic acid (PALA) and 5-fluorodeoxycytidine (FdC), the levels of CldC-derived RNA and DNA directed metabolites increased in tumor and decreased in normal tissues compared to when CldC was administered alone. These modulators inhibit the de novo pathway of thymidine biosynthesis, lowering thymidine triphosphate (TTP) levels, which compete with CldUTP for incorporation into DNA. 5-Benzylacyclouridine (BAU), an inhibitor of uridine phosphorylase, was also utilized. DNA incorporation studies using C3H mice bearing RIF-1 tumors showed that the extent of incorporation of 5-chlorodeoxyuridine (CldU) into DNA correlates with the levels of cytidine and dCMP deaminases; this is encouraging in view of their high activity in many human malignancies and the low activities in normal tissues, including those undergoing active replication. Up to 3.9% replacement of thymidine by CldU took place in RIF-1 tumors, whereas incorporation into bone marrow was below our limit of detection. CldC did not result in photosensitization under conditions in cell culture in which radiosensitization to X rays was obtained. Thus, the combination of CldC with modulators of its metabolism has potential as a modality of selective radiosensitization for ultimate clinical use in a wider range of tumors than those of the brain.
...
PMID:Radiation, pool size and incorporation studies in mice with 5-chloro-2'-deoxycytidine. 239 14

3'-Azido-2',3'-dideoxythymidine (AZT) and 2',3'-didehydro-2',3'-dideoxythymidine (D4T) are potent and selective inhibitors of human immunodeficiency virus replication in MT-4 and ATH8 cells. They are also inhibitory to the replication of murine retroviruses, i.e. Moloney murine sarcoma virus-induced transformation of C3H cells. In MT-4 cells AZT is readily phosphorylated to its 5'-monophosphate, while the 5'-di- and 5'-triphosphates are generated to a 200-600-fold lower extent than the 5'-monophosphate. D4T is phosphorylated in MT-4 cells to its 5'-monophosphate at a 300-600-fold lower extent than AZT. The phosphorylation of AZT in the thymidine kinase-deficient cell line (Raji/TK-) is severely depressed, while D4T phosphorylation is only slightly diminished in Raji/TK- as compared to Raji/0 cells. D4T has a 10-fold lower affinity for phosphorylation by crude MT-4 cell extracts than AZT (Km, 142 and 14 microM, respectively), and the Vmax for phosphorylation of D4T is only 5% that of AZT. D4T is phosphorylated by MT-4 cell extracts about 180-fold less efficiently than AZT (Vmax/Km, 0.06 for D4T, as compared to 11 for AZT), and this is consistent with the differences found in the amounts of phosphorylated products of D4T and AZT formed in intact MT-4 cells. The 5'-triphosphates of AZT and D4T are equipotent in their inhibitory effects on the reverse transcriptases from human immunodeficiency virus and Moloney murine leukemia virus.
...
PMID:Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. 253 71


1 2 3 4 5 Next >>

---