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)

RADA-1 cells (H-2a), a murine leukemia cell line maintained by serial transfer in histocompatible recipients expressing thymus-leukemia (TL) 1, 2, 3 antigenic determinants, resisted the cytotoxic effects of guinea pig complement (GPC) and TL antiserum. The cells expressed a lower density of TL antigens than did ASL-1 cells, another TL(+) leukemia cell line expressing the same determinants and susceptible to complement (C)-mediated lysis. Stable somatic cell hybrids of RADA-1 cells and LM(TK)- cells (H2k), a TL(minus) thymidine kinase-deficient mutant of mouse L cells, were selected in hypoxanthine-aminopterin-thymidine medium. The hybrid cells expressed the H-2 antigens of both parents and shared a hybrid karyotype. They formed TL 1, 2, 3 antigens as determined by immunofluorescence, mixed hemagglutination methods, the direct isolation of TL antigens from Nonidet P40 extracts of the cells, and the capacity of the cells to reduce by absorption the known titers of TL antiserum. These hybrid cells lost the capacity to resist lysis by TL antiserum and GPC. They were susceptible to the cytotoxic effects of TL 1, 2, 3; TL 2; OR TL 1, 3 antiserum and GPC, even though the density of TL antigens associated with the cells was approximately 25% of their resistant RADA-1 parental cells. These results indicated that the mechanism of resistance to C-mediated lysis was genetically separable from the expression of TL antigens by the cells and that the susceptibility of the cells to the cytotoxic effects of antiserum was related only in part to the density of TL antigens expressed by the cells.
J Natl Cancer Inst 1975 Aug
PMID:Complement sensitivity of somatic hybrids of a complement-resistant murine leukemia cell line. 5 Oct 86

Herpes simplex virus (HSV)-related antigens have been demonstrated in the nuclei and cytoplasm of human and mouse cells biochemically transformed by ultraviolet light-irradiated HSV. This was accomplished by using peroxidase/anti-peroxidase immunological staining and indirect immunofluorescence with rabbit antisera that had high neutralizing titers against the HSV-specific thymidine kinase activity and virus infectivity. HSV-1 antisera reacted with antigens in cells biochemically transformed by type 1 HSV, but not with those of cells biochemically transformed by type 2 HSV. Similarly, HSV-2 antisera reacted with antigens in cells biochemically transformed by HSV-2, but not with those in cells biochemically transformed by HSV-1. In contrast, herpes virus-related antigens were detected in cells cytolytically infected with HSV-1 and with HSV-2 by either type 1 or type 2 HSV antisera. These observations suggest that the antigens detected in the biochemically transformed cells were a type-specific subset of the HSV-related antigens synthesized in cells undergoing productive infection by HSV-1 and HSV-2.
Int J Cancer 1977 Sep 15
PMID:Detection of herpes simplex virus-related antigens in the nuclei and cytoplasm of biochemically transformed cells with peroxidase/anti-peroxidase immunological staining and indirect immunofluorescence. 7 Dec 79

The influx of 1.0 muM 5-fluoro[6-3H]deoxyuridine (5F[6-3H]dUrd) into L5178Y mouse leukemia cells followed a linear function with time from 2 to 10 min. Ammonium 5-bromodeoxyuridine 5'-methylphosphonate (BrdUrd-OPO2Me) inhibited the membrane transport of 5F[6-3H]dUrd into L5178Y cells. Influx of 5F[6-3H]dUrd into inhibited cells was observed from zero to 3 min; after 3 min the net rate of 5F[6-3H]dUrd uptake into the cells treated with 18 muM BrdUrd-OPO2Me was almost zero. The cellular uptake of 2'-deoxy[6-3H]uridine or 5-bromo[6-3H]deoxyuridine was inhibited by BrdUrd-OPO2Me. The L5178Y cells were grown for 96 hr in a medium that contained tritium-labeled BruDur-OPO2Me. An analysis of the labeled products in the growth medium showed that the ester linkage is not cleaved to separate the [3H]methylphosphonate group and the nucleoside moiety of BrdUrd-OPO2[3H]Me. The activity of thymidine kinase in a cell-free preparation from L5178Y cells was demonstrated. Although 37 muM 5-bromo-2'deoxyuridine produced an inhibition of approximately 45% in kinase activity, BrdUrd-OPO2Me had no effect on enzyme activity. The results indicate that BrdUrd-OPO2Me is an inhibitor of the cell membrane transport of the 5-fluoro and 5-bromo derivatives of 2'-deoxy[6-3H]uridine.
Cancer Res 1976 Sep
PMID:Inhibition of membrane transport of 5-fluoro[6-3H]deoxyuridine into L5178Y mouse leukemia cells. 13 41

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.
Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1977 Jan 21
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

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, under the application of hyperthermia, vitamin K and cytocidal agents show: The effect of hyperthermia and menadion (the basic substance of the K vitamins) on the above parameters of dNTP synthesis can explain the labile effects of hyperthemia and vitamin K therapy on cancer growth. Alterations of the dNTP concentrations and demonstrable or absent inhibition of the ribonucleotide reduction with application of fluoruracil, amethopterine, cytosine arabinoside, hydroxyurea, trisethylen iminobenzochinone and daunomycin confirm and supplement our knowledge of the cytostatic action mechanism of these substances. They show moreover by the example of fluoruracil and amethopterine medication that the dTTP concentration estimation after in-vitro incubation of tumour cells with the addition of FU or methotrexat is a better measurement of the therapeutic in-vivo responsiveness of malignant tumours than the previously performed test methods.
Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1977 Jan 21
PMID:[Studies on the thymidine-triphosphate synthesis in malignant tumors. II. Effect of hyperthermia, Vitamin K and Cytotoxic agents (author's transl)]. 13 37

Methods have been developed to assay several aspects of 5-fluoro-2'-deoxyuridine and 5-fluorouracil metabolism in tissue culture cells. These methods allow measurement of (a) intracellular levels of the covalent complex formed between 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), 5,10-methylenetetrahydrofolate, and thymidylate synthetase; (b) incorporation of drug into RNA; and (c) analysis of drug metabolites. The methods were developed using radioactively labeled drugs, but they should be adaptable to studies using nonlabeled compounds. Sephadex G-25 chromatography or trichloroacetic acid precipitation were utilized for isolation of the macromolecular cell fraction; prior treatment of this fraction with RNase or heating at 65 degrees for 15 min resulted in selective removal of RNA or the thymidylate synthetase complex, respectively, from the precipitable fraction. Free intracellular drug metabolites present in the acid-soluble fraction were analyzed by high-pressure liquid chromatography. Following incubation of HTC cells with [6-3H]-5-fluoro-2'-deoxyuridine, a radioactive macromolecule was isolated and identified as a FdUMP-5,10-methylenetetrahydrofolate-thymidylate synthetase complex. Intracellular formation of this complex was shown to be dependent on the presence of the enzyme thymidine kinase. Dissociation of the complex in vivo was first order with a t1/2 of 6.2 hr; in contrast, a t1/2 of 2 hr was determined for dissociation of the complex in cytosol. Incubation of L1210 cells with [6-3H]-5-fluorouracil for 22 hr resulted in formation of 80 fmol of FdUMP-5,10-methylenetetrahydrofolate-thymidylate synthetase complex per 10(6) cells, as compared with 400 fmol of drug incorporated into RNA per 10(6) cells. Intracellular FdUMP could not be detected in the acid-soluble fraction of these cells unless the cells were first heated to dissociate the complex.
Cancer Res 1979 Sep
PMID:Assay of intracellular free and macromolecular-bound metabolites of 5-fluorodeoxyuridine and 5-fluorouracil. 15 5

A cytoplasmic form of thymidine kinase was detected in sera from rats bearing Morris hepatoma 7777. Polyacrylamide electrophoretic properties demonstrate similarity between the serum enzyme extracted from hepatoma tissue. This form of thymidine kinase has also been described in normal human fetal tissue and a variety of human tumor cells. The results suggest that serum isoenzymes of thymidine kinase may be a useful adjunctive test for the presence of certain types of malignant tumors.
Cancer Res 1976 Jun
PMID:Tumor-associated thymidine kinase in the sera of rats with transplanted hepatomas. 17 42

The bioreductive alkylating agent, 2,3-bis(chloromethyl)-1,4-napthoquinone (CMNQ), has been shown to inhibit the growth of Sarcoma 180 ascites cells in vivo. Evidence for the reductive activation of this agent via the mitochondrial respiratory chain was provided by CMNQ-induced oxidation of reduced nicotinamide adenine dinucleotide; the interaction was shown to be on the substrate side of the site of rotenone inhibition. Consistent with the concept that reduction of CMNQ to a hydroquinone results in the generation of an alkylating species (i.e., a quinone methide) was the finding that radioactivity from [14C]CMNQ present in Sarcoma 180 ascites cells was associated with DNA, RNA, and protein for a period of up to 72 hr after exposure to tumor-bearing animals to this agent. Inhibition of the incorporation of [3H]thymidine, [3H]uridine, and [14C]leucine into DNA, RNA, and protein, respectively, of Sarcoma 180 ascites cells was produced by this agent, with DNA biosynthesis being the most susceptible. The inhibitory effect of CMNQ on the formation of DNA was, at least in part, the result of a prevention of the conversion of thymidine to its nucleotide forms. This action was due to (a) a drug-induced decrease in intracellular levels of adenosine 5'-triphosphate, presumably resulting from uncoupling of oxidative phosphorylation by CMNQ; and (b) a partial loss of thymidine kinase activity in Sarcoma 180 cells, which did not appear to be due to direct inhibition of the enzyme by the drug. Although the primary event produced by CMNQ at the mitochondrial level appeared to be release of respiratory control, other effects of mitochondrial metabolism occurred. These included inhibition of reduced nicotinamide adenine dinucleotide and succinoxidase activities, as previously demonstrated, and mitochondrial swelling, which suggested interaction of CMNQ with the inner mitochondrial membrane. These findings indicate a variety of biochemical lesions are associated with the antineoplastic activity of CMNQ and demonstrate a relationship between the effects of this drug on mitochondrial respiratory control and DNA biosynthesis.
Cancer Res 1976 Nov
PMID:Mode of action of the bioreductive alkylating agent, 2,3-bis(chloromethyl)-1,4-naphthoquinone. 18 23

The current state of knowledge concerning the biochemical transformation by Herpes Simplex virus (HSV) of mammalian cells lacking the enzyme thymidine kinase (TK) is reviewed. Transformation of thymidine kinase negative mouse cells (LTK-) to the TK+ phenotype by ultraviolet light-inactivated HSV preparations depends both on the irradiation dose and on the multiplicity of infection. Once stably associated with the transformed cell, the HSV thymidine kinase appears to be regulated differently than the cellular enzyme: HSV TK activity is maximal in stationary cells, whereas cellular TK activity is maximal during the S-pphase of growing cells. Furthermore, infection with an HSV TK- mutant virus leads to the induction of TK activity in HSV TK+ cells, but not in normal TK+ cells. Recent studies indicate that in addition to the TK gene, at least one other HSV gene, perhaps a structural antigen of the virion, is also transferred to TK- cells. This is consistent with the finding that a clone of HSV TK+ cells harbors approximately five copies per cell of 23 per cent of the HSV genome.
Bull Cancer
PMID:Thymidine kinase gene transfer by herpes simplex virus. 18 68

Considerable thymidine kinase and pyrroline-5-carboxylate reductase activities were found in the plasma of rats bearing a transplanted lymphoma; neither activity was detected in plasma of hosts carrying hepatic, renal, mammary, or submaxillary gland tumors. All host livers exhibited signs of biochemical immaturity as indicated by the appropriate increases or decreases in the concentrations of the nine enzymes measured. The extent and time schedule of the changes in host liver varied with the enzyme and with the tumor that caused them. The hepatic concentrations of ornithine aminotransferase, arginase, pyrroline-5-carboxylate reductase, and glucokinase (all diminished), and of peptidyl proline hydroxylase and hexokinase (increased) were sensitive indicators of tumor growth in general. The concentration of ornithine aminotransferase decreased before the tumors became palpable. At more advanced stages, the high hepatic thymidine kinase activity distinguished the presence of hepatoma and lymphoma from those of all other equally fast-growing tumors. However, only in lymphoma-bearing rats did a fivefold elevation of hepatic thymidine kinase occur as early as 4 days after implantation. Additional observations on the lymphoma itself, on blood cells, and on the involuting thymus of normal rats indicate that the striking systemic effects of this tumor cannot be explained by a release of enzymes from the thymus or by the increased number of lymphoma cells present in blood or liver.
Cancer Res 1977 Jan
PMID:The effect of lymphoma and other neoplasms on hepatic and plasma enzymes of the host rat. 18 34


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