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

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

Recent reports by several laboratories indicate that not all non-essential target loci are equally capable of detecting chromosomal mutations. The present study was undertaken to determine if both the tk locus in mouse lymphoma cells and the hgprt locus in Chinese hamster ovary (CHO) cells can be used to quantitate chromosomal mutations. Seven known mutagens for the tk locus were selected. These compounds were evaluated in the mouse lymphoma assay and in a suspension adapted CHO assay for their mutagenicity. In addition to the specific locus mutagenesis analysis, mouse lymphoma and CHO cells were evaluated for the frequency of gross chromosome aberrations. From these investigations, it appears that only those compounds [2-methoxy-6-chloro-9-(3-[ethyl-2-chloroethyl] aminopropylamino)-acridine-dihydrochloride (ICR 170), ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS)] that induce significant numbers of large-colony thymidine kinase (TK) mutants also induce significant numbers of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) mutants. The four acrylates evaluated (methyl acrylate, ethyl acrylate, trimethylolpropane triacrylate and tetraethyleneglycol diacrylate) induced almost exclusively small-colony TK mutants and very few if any HGPRT mutants. Aberration analysis revealed that both the mouse lymphoma and CHO cells responded to the clastogenicity of the compounds (except for ICR 170 which was not positive in CHO cells) and that neither cell line was clearly more sensitive than the other to the clastogens tested. It is significant that the four acrylates give little or no evidence of genotoxicity when evaluated using selection for HGPRT-deficient mutants, yet are clearly clastogenic to the same cells in the same experiment. These results are consistent with the hypothesis that the hgprt locus may not be useful as a marker to evaluate the clastogenic component of a genotoxic compound. The present study adds to the increasing number of studies that support the view that the hemizygous nature of the hgprt locus permits the recovery of mutations primarily affecting the function of a single gene; whereas the heterozygous nature of the tk locus permits the recovery of both single gene and chromosomal mutations.
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PMID:Differential mutant quantitation at the mouse lymphoma tk and CHO hgprt loci. 268 35

Glucocorticoids inhibit the proliferation of murine T-lymphoma P1798 cells. P1798 cells do not die in the presence of dexamethasone, and the process of inhibition of proliferation is completely reversible. As cells cease to divide, expression of a number of genes is inhibited. Among these are genes the expression of which is regulated in some manner that is linked to cell proliferation. We have undertaken to study the mechanism whereby glucocorticoids inhibit the expression of genes in P1798 cells. Three model systems will be reviewed. In all cases, these appear to be examples of secondary regulation. Glucocorticoid-mediated inhibition of transcription of the DNA encoding ribosomal RNA (rDNA) has been investigated in some detail. The data indicate that dexamethasone causes a decrease in the amount or activity of an RNA polymerase I transcription initiation factor. This factor exhibits a short biological half-life and the data are consistent with the hypothesis that glucocorticoids regulate the synthesis of this transcription factor. The gene encoding thymidine kinase appears to be regulated in a similar fashion. On this basis, we propose that glucocorticoids may have the general property of regulating the synthesis of certain transcription factors. Glucocorticoids also regulate the translation of a certain class of mRNAs, including those that encode ribosomal proteins. These are characterized by a low efficiency of translation in untreated cells. Upon exposure to dexamethasone, the translation of these mRNAs is disproportionately inhibited. We speculate that translation of the mRNAs encoding certain transcription factors may be regulated in a similar fashion. Specifically, we propose that transcription of certain proliferation-related genes may be dependent upon factors of short biological half-life. These are encoded by mRNAs that are poorly translated under optimal growth conditions. Any slight perturbation in translation efficiency, as caused by glucocorticoids, results in a disproportionate inhibition of synthesis of these hypothetical transcription factors. Transcription of a class of proliferation-related genes ceases as a result.
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PMID:Glucocorticoid inhibition of gene expression and proliferation of murine lymphoid cells in vitro. 270 66

Mouse lymphoma cells of the L5178Y TK+/- -3.7.2C line were exposed to sidestream and mainstream cigarette smoke condensates (CSC). Cells which survived the trifluorothymidine (TFT) challenge fell in 2 classes: large- and small-colony formers. Southern blot analysis of NcoI-digested DNA from mutant colonies yielded 2 distinct restriction fragment banding patterns when probed with the thymidine kinase (TK) cDNA clone pMtk4. One such pattern was composed of 4 bands at 6.4, 5.5, 4.7 and 2.9 kilobase pairs (kb) and was identical to that of TK+/- controls. A second pattern differed from the first only in the absence of the 6.4-kb band. The majority (83/95) of both large and small colonies derived from cells exposed to CSC exhibited restriction fragment banding patterns lacking the 6.4-kb band. The data from the present study suggest that there is no association between mutant colony size and the presence of the 6.4-kb NcoI restriction fragment at the TK locus in the mouse lymphoma mutants analyzed.
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PMID:Preliminary molecular analysis of the TK locus in L5178Y large- and small-colony mouse lymphoma cell mutants. 276 66

Four chemical preservatives commonly used in ophthalmic solutions were tested for their toxic and mutagenic potential in mouse lymphoma cells with and without exposure of the cells to ultraviolet A (UVA) radiation. The preservatives tested were benzalkonium chloride (BAK), chlorhexidine, thimerosal and ethylenediaminetetraacetic acid (EDTA). Cell survival and mutagenesis were measured using the L5178Y mouse lymphoma (TK +/-) system. Cells were exposed to varying amounts of preservatives for 1 h at 37 degrees C, and then aliquots were irradiated with UVA radiation (during the exposure to preservative). Cells were then assayed for survival, and for mutagenesis at the thymidine kinase (TK) locus. In concentrations commonly found in ophthalmic solutions, BAK, chlorhexidine, and thimerosal were toxic to cells, and thimerosal was slightly mutagenic. When cells were exposed to preservative and UVA radiation, chlorhexidine was mutagenic and the mutagenic activity of thimerosal was enhanced.
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PMID:Cytotoxicity and mutagenicity of ophthalmic solution preservatives and UVA radiation in L5178Y cells. 278 Aug 30

We evaluated the ability of the antitumor agent 4-(9-acridinylamino)-methanesulfon-m-anisidide (amsacrine or m-AMSA) and its congener, o-AMSA, to induce specific-locus mutations at the heterozygous thymidine kinase (tk) locus of L5178Y/TK+/- -3.7.2C mouse lymphoma cells. These cells permit the recovery of mutants due to single-gene or chromosomal mutation. m-AMSA was highly mutagenic at the tk locus, producing approximately 3000 mutants/10(6) survivors at 10% survival; positive dose range 1-10 ng/ml; o-AMSA produced approximately 1500 mutants/10(6) survivors at 10% survival; positive dose range 0.1-2.5 micrograms/ml. Most of the TK mutants were small colonies, which suggests that m-AMSA and o-AMSA induce primarily chromosomal mutations as opposed to single-gene mutations. The potent clastogenicity of these agents was confirmed by cytogenetic analysis for chromosomal aberrations, which showed that m-AMSA (9 ng/ml, 10% survival) and o-AMSA (1 microgram/ml, 10% survival) produced 383 and 179 aberrations, respectively, per 100 metaphases (background = 3-4/100). The large-colony TK mutant frequencies produced by m-AMSA (67 - 112/10(6) survivors; background = 7/10(6); survival = 63 - 16%) were comparable to the published HPRT mutant frequencies produced by m-AMSA in V79 cells. Novobiocin (50 micrograms/ml), an inhibitor of mammalian DNA topoisomerase II and other enzymes, inhibited the mutagenic effects of m-AMSA, suggesting that DNA topoisomerase II (or another enzyme) may play a role in the mutagenic/clastogenic activity of m-AMSA.
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PMID:Mutagenicity of m-AMSA and o-AMSA in mammalian cells due to clastogenic mechanism: possible role of topoisomerase. 283 Apr 52

Using the L5178Y mouse lymphoma cell thymidine kinase locus and the Salmonella his locus assays, the mutagenic potentials of several catecholamines and related compounds were examined. No supplementary metabolic activation systems were used. In the mouse lymphoma assay, the dihydroxybenzenes catechol and hydroquinone had similar and appreciable mutagenic potentials, whereas resorcinol was less active. Derivatives of catechol, such as dopamine and epinephrine, were mutagenic, whereas the related monohydroxylated compounds tyramine and synephrine were inactive. The primary amine, arterenol, and the corresponding secondary amine, epinephrine, induced similar mutagenic responses. Carboxylation of the side chain of dopamine, giving L-dopa, reduced the maximum mutagenic response. The introduction of charged groups directly on to the aromatic ring also reduced mutagenic activity, while an intervening methylene reversed this effect. Thus, 3,4-dihydroxyhydrocinnamic acid was more active than 3,4-dihydroxybenzoic acid. The compound active at the lowest doses was 4-tert-butyl catechol. The activities of these compounds are highly dependent upon substituent groups. Experiments with superoxide dismutase gave circumstantial evidence for some of the mutagenic activity being due to superoxide anion. Active oxygen species might be responsible for some of the observed effects, but this cannot be concluded from the superoxide dismutase experiments. Mutagenic responses in Salmonella were very low but were significant for L-dopa in three strains and for epinephrine and arterenol in one strain. Limited DNA association studies of 14C-dopamine suggest interactions in L5178Y and Salmonella cells and in mouse liver. The mutagenicity of dopamine in L5178Y is reduced by high serum concentrations during the exposure period, while the apparent association with DNA is unaffected.
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PMID:Reactivity of catecholamines and related substances in the mouse lymphoma L5178Y cell assay for mutagens. 283 91

Cultured P388/S mouse lymphoma cells resistant to 5-bromodeoxyuridine (BUdR) and deficient in thymidine kinase (TK-) were fused with P388/DAG cells resistant to 1,2:5,6-dianhydrogalactitol (DAG), an anticancer alkylating agent, and to 6-thioguanine (6-TG) and deficient in hypoxanthine phosphoribosyl-transferase (HPRT-). Sensitivity to DAG in the hybrid line was very close to that in the P388/DAG line, which means that resistance to DAG was inherited in a quasi-dominant manner. Hybrid cells showed cross-resistance, similar to that of the DAG-resistant line, to two other hexitols, dibromodulcitol (DBD) and disuccinyldianhydrogalactitol (DisuDAG).
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PMID:Dominance of resistance to the alkylating agent 1,2:5,6-dianhydrogalactitol in P388 mouse lymphoma hybrid cells. 290 89

The behavior of the activities of thymidine metabolizing enzymes, dihydrothymine dehydrogenase (EC 1.3.1.2) and thymidine phosphorylase (EC 2.4.2.4) for thymidine degradation, thymidine kinase (EC 2.7.1.75) and thymidylate synthase (EC 2.1.1.45) for DNA synthesis, was elucidated in cytosolic extracts from normal human lymphocytes and 13 human leukemia-lymphoma cell lines. In the normal human lymphocytes, the activities of dihydrothymine dehydrogenase, thymidine phosphorylase, thymidine kinase, and thymidylate synthase were 6.88, 796, 0.30, and 0.29 nmol/h/mg protein, respectively. In leukemia-lymphoma cell lines, the activities of synthetic enzymes, thymidine kinase, and thymidylate synthase, increased two- to 79-fold and 22- to 407-fold of the normal lymphocyte values. In contrast, the activities of the catabolic enzymes, dihydrothymine dehydrogenase and thymidine phosphorylase, decreased to 5-42% and 3-38% of the values of normal lymphocytes. As a result, the ratio of activities of thymidine kinase/dihydrothymine dehydrogenase was elevated by 7- to 1170-fold, respectively. Thus, reciprocal behavior in the activities of the opposing enzymes in thymidine metabolism was observed in human leukemia-lymphoma cells. Polyclonal and monoclonal antibodies against dihydrothymine dehydrogenase were prepared and studies on immunotitration of this enzyme with these antibodies showed that the enzyme protein amount in Jurkat leukemic cells was 36% of that of normal lymphocytes. This was in good agreement with the decrease in the activity of the enzyme to 32%, indicating that the decrease in activity in the leukemic cells was due to the decline in the amount of enzyme protein. The metabolic imbalances in thymidine utilization appear to be characteristic of human leukemia-lymphoma cells. These observations should confer selective advantages to the lymphoproliferating cells and mark out the catabolic, as well as the synthetic, enzymes as important targets in the design of chemotherapy.
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PMID:Behavior of activities of thymidine metabolizing enzymes in human leukemia-lymphoma cells. 291 46

Two dyes (C.I. Solvent Yellow No. 33 and a mixture of C.I. Solvent Yellow No. 33 and C.I. Solvent Green No. 3) were tested for mutagenicity in the Salmonella reversion assay and the L5178Y/TK+/- mouse lymphoma assay, and also for sister chromatid exchange (SCE) induction in vivo in C57B1/6J mice. In addition, a greater than 99.9% pure sample of the yellow dye [2-(2'-quinolyl)-1,3-indandione] was tested with and without exogenous activation in the Salmonella reversion assay and the L5178Y/TK+/- mouse lymphoma assay. Neither C.I. Solvent Yellow No. 33 nor the C.I. Solvent Yellow No. 33 and Solvent Green No. 3 mixture was positive for inducing SCEs in vivo. All three dyes were tested in the standard plate incorporation test in seven Salmonella strains TA98, TA100, TA102, TA104, TA1535, TA1537, and TA1538. The dyes were negative with and without exogenous activation in TA98, TA1535, and TA1538. One test with TA1537 was positive with the greater than 99.9% purified yellow dye. All three dyes gave weakly positive results (less than a twofold increase) with S-9 in TA100 and were clearly positive in TA102 and TA104 both with and without S-9. They also induced mutation at the thymidine kinase locus in mouse lymphoma cells, produced both large- and small-colony trifluorothymidine-resistant mutants, and were clastogenic. The purified yellow dye was further tested for SCE induction in mouse lymphoma cells and was determined to give a slightly positive response in the presence of S-9.
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PMID:Mutagenic screening of marker grenade dyes by the Salmonella reversion assay, L5178Y/TK+/- mouse lymphoma assay, and in vivo sister chromatid exchange analysis in mice. 304 84

We have studied the serum beta 2-microglobulin (beta 2m) and thymidine kinase (TK) levels in 19 newly diagnosed lymphoma patients. The proportion of the S-phase cells (SPF) was determined by flow cytometry from subsequently taken tumor biopsy material. A positive correlation between SPF and TK (r = 0.4, P = 0.1), but not between SPF and beta 2m, was seen in the whole material. Sixty-three percent of the high-grade malignancy non-Hodgkin lymphomas (5/8) showed high proliferative activity in both the SPF and TK analyses. Furthermore, high tumor SPF and enhanced serum TK levels reflected equally well and consistently the clinical outcome of the underlying disease.
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PMID:Correlation between tumor proliferation and serum levels of beta 2-microglobulin and thymidine kinase in malignant lymphomas. 305 29


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