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)

The clinical significance of plasma cell acid phosphatase (PCAP) was evaluated in 143 patients with monoclonal gammapathies, using a semiquantitative cytological scoring method. Significantly higher PCAP scores were measured in overt myelomas than in MGUS or in smouldering myelomas, during the phases of activity (diagnosis, progression, relapse), and in patients with extended disease. Among various clinical and laboratory parameters, PCAP was significantly related to the percentage of bone marrow plasma cells, the neoplastic growth fraction, as determined by Ki67 monoclonal antibody, and to serum levels of C-reactive protein. An inverse relationship was also found between PCAP and hemoglobin levels. Although the patients with "flaming" plasma cells exhibited low PCAP scores and poor prognosis, on the whole, myeloma patients with PCAP scores < 200 showed a significantly longer median overall survival than those with PCAP > 200 (46 vs 20 months, p < 0.003). However, in the multivariate analysis, beta 2-microglobulin, growth fraction, performance status, and serum levels of thymidine kinase and C-reactive protein, but not PCAP, maintained a significant prognostic relevance. In conclusion, although PCAP may be considered a marker of disease activity, other parameters provide better prognostic information in myeloma patients.
Leuk Lymphoma 1994 Aug
PMID:Plasma cell acid phosphatase and prognosis in multiple myeloma. 781 11

The mouse lymphoma (L5178Y tk+/- 3.7.2C) in vitro mutagenesis assay can measure the genotoxic effects of a wide variety of chemical agents by inactivation of a single functional thymidine kinase (tk-1) gene. We have previously demonstrated, using cytogenetic and molecular techniques, that the types of molecular lesions associated with tk-1 gene inactivation span a wide range similar to that seen in tumor cells at specific oncogene and tumor suppressor gene loci. We have identified, using polymerase chain reaction techniques, 21 microsatellite, or 'simple sequence repeat', polymorphisms between chromosomes 11a and 11b in 3.7.2C cells. These microsatellite polymorphisms span virtually the entire chromosome, from mapping positions of 3-78 centiMorgans (cM) from the centromere, thus providing landmarks to study loss of genetic material across the entire chromosome. Four of the microsatellite polymorphisms lie within 12 cM of tk-1, and provide a means of mapping loss of genetic material in the immediate vicinity of tk-1, a capability that we have not previously had in the mouse lymphoma assay. Loss of alleles (i.e. loss of heterozygosity) is an important feature of tumor development, having to do with tumor suppressor gene expression. Therefore, the ability to detect loss of heterozygosity in the mouse lymphoma assay will make the assay an extremely valuable tool in the detection of agents capable of inducing loss of heterozygosity.
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PMID:Use of microsatellite DNA polymorphisms on mouse chromosome 11 for in vitro analysis of thymidine kinase gene mutations. 783 76

Cultured P388/VCR mouse lymphoma cells resistant to vincristine (VCR) and 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-). The hybrid cells expressed multidrug resistance (MDR), i.e., resistance to VCR and cross-resistance to Adriamycin (ADM) and actinomycin D (Act. D), in a dominant manner. The presence of glycoprotein p170, the MDR gene product, was detected in the hybrid cells. Resistance to DAG was also expressed dominantly, whereas cross-resistance to dibromodulcitol (DBD), a chemically related anticancer drug, was slight.
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PMID:Dominant expression of multidrug resistance in intraspecific murine lymphoma hybrid cells. 790 24

Glucocorticoids inhibit transcription of the proto-oncogene c-myc in lymphoid cells of thymic origin. To determine if this effect is associated with changes in the properties of the transcription factor E2F, extracts were prepared from control and glucocorticoid-treated P1798 murine T lymphoma cells, and the macromolecular state of E2F was assessed by gel-mobility shift. Control extracts exhibit two predominant gel-mobility shift entities of which one corresponds to "free" E2F. A second entity, complex C, has properties similar to those described for the complex containing E2F, p107, cyclin A, and Cdk2. Complex C disappears after addition of dexamethasone and is replaced by complex D. The mobility of this complex and its sensitivity to SV40 T antigen suggest that complex D corresponds to an E2F-p105Rb-1 complex. Extracts from control and glucocorticoid-treated cells yield identical DNase I protection patterns on the c-myc P2 promoter. Furthermore, such extracts transcribe the c-myc P2 promoter in vitro with equal activity. The relative abundance of the E2F complexes was measured after addition of dexamethasone. Complex C disappears as cells withdraw from S phase, and complex D appears at this time. The genes encoding thymidine kinase (Tk-1) and p34cdc2 (cdc2) are regulated with kinetics similar to those observed for changes in the macromolecular state of E2F. However, regulation of c-myc expression occurs long before any change in E2F. The macromolecular state of E2F may regulate expression of genes at the G1/S boundary. However, the data are not consistent with the hypothesis that association of E2F with tumor suppressor gene products such as p107 or p105Rb-1 is relevant to glucocorticoid regulation of c-myc transcription.
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PMID:The macromolecular state of the transcription factor E2F and glucocorticoid regulation of c-myc transcription. 800 8

Allogeneic bone marrow transplantation (BMT) is associated with a severe complication--graft-versus-host disease (GVHD). Although effectively preventing GVHD, ex vivo T-lymphocyte marrow depletion unfortunately increases graft rejection and reduces the graft-versus-leukemia (GVL) effect. The ex vivo transfer of the herpes simplex thymidine kinase (HS-tk) suicide gene into T cells before their infusion with hematopoietic stem cells could allow for selective in vivo depletion of these T cells with ganciclovir (GCV) if subsequent GVHD was to occur. Thus, one could preserve the beneficial effects of the T cells on engraftment and tumor control in patients not experiencing severe GVHD. To obtain T cells specifically depleted by GCV, we transduced primary T cells with a retroviral vector containing the HS-tk and neomycin resistance (NeoR) genes. Gene transfer was performed by coculturing PHA +/- CD3- or alloantigen-stimulated purified T cells on an irradiated retroviral vector producer cell line or by incubating the T cells in supernatant from the producer. Subsequent culture in G418 for 1 week allowed for the selection of transduced cells. GCV treatment of interleukin-2-responding transduced and selected cells resulted in greater than 80% growth inhibition, whereas GCV treatment of control cells had no effect. Similarly, the allogeneic reactivity of HS-tk-transduced cells was specifically inhibited by GCV. Combining transduced and nontransduced T cells did not show a bystander effect, thus implying that all of the cells inhibited by GCV were indeed transduced. Lastly, studies involving the transduction of the HUT-78 (T-lymphoma) cell line suggest that stable expression of HS-tk can be maintained over 3 months in vitro in the absence of G418. In summary, we have established the feasibility of generating HS-tk-transduced T cells for subsequent in vivo transfer with hematopoietic stem cells and, if GVHD occurs, specific in vivo GCV-induced T-cell depletion in allogeneic BMT recipients.
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PMID:Ganciclovir treatment of herpes simplex thymidine kinase-transduced primary T lymphocytes: an approach for specific in vivo donor T-cell depletion after bone marrow transplantation? 804 49

The suspect human carcinogen, etoposide, is known to be genotoxic, producing both gene and chromosomal mutations, probably by virtue of its ability to inhibit topoisomerase II activity. The present paper describes assays conducted using the Salmonella assay, the mouse lymphoma tk+/- assay (gene and chromosomal mutation analysis and molecular analysis of tk-/- mutants) and the mouse bone marrow micronucleus assay. Nonreproducible, weak, dose-related increases in mutation frequency in strain TA98 (but not TA1538 or TA1537) of Salmonella typhimurium were observed. Etoposide was highly mutagenic at the heterozygous thymidine kinase (tk+/-) locus of L5178Y mouse lymphoma cells at concentrations below 0.1 micrograms/ml. Mostly small colony mutants were induced, consistent with the potent clastogenicity also observed. Molecular analysis of mutants indicated that 83% and 92% of large and small colony mutants, respectively, had lost the entire target gene sequence. Chromosomally aberrant L5178Y cells were approximately 2 to 600-fold more prevalent than small tk-/- mutant colonies. This suggests that the viable target for etoposide-mediated clastogenesis in the selective assay is approximately one-fifth of chromosome 11b, itself being approximately one-fortieth of the mouse genome. An unusually potent response was observed for etoposide in the mouse bone marrow micronucleus assay (63.1 +/- 18 MPE/1,000 PE 24 hours after an oral dose of 1 mg/kg). The minimum detectable dose level in the assay was between 0.01 and 0.1 mg/kg. At dose levels between 1 and 15 mg/kg, an inverse dose response was observed. This reduction in assay response was not due to the small concommitant decrease in the incidence of polychromatic erythrocytes, a conclusion based on studies with N-methyl-N-nitrosourea. Animals sampled 48 hours after dosing with etoposide (10 mg/kg) had no polychromatic erythrocytes in the bone marrow. These observations for the micronucleus assay await explanation. The chemical structure of etoposide is displayed and discussed within the context of such strong mutagenic activity being associated with a nonelectrophilic agent.
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PMID:Potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: comparison to Salmonella responses. 773 7

The expression of nucleoside transporters is a limiting factor in the pharmacology of the nucleoside analogue, cytosine arabinoside (AraC) and is associated with cellular proliferation. We investigated the expression of nucleoside transporters on plasma cells from the bone marrow of 51 patients with multiple myeloma by 2-colour immunofluorescence flow cytometry, utilising 5-(SAENTA-x8)-fluorescein, a fluorescent ligand for the nucleoside transporter and anti-CD38 conjugated to phycoerythrin, as CD38 expression has unique characteristics on plasma cells. Mean nucleoside transporter expression on bone marrow plasma cells from patients with myeloma (1777 +/- 2181 transporters/plasma cell) was not significantly different from expression on plasma cells from normal bone marrow (997 +/- 1096 transporters/plasma cell). However, analysis of disease subgroups revealed a significant trend towards increased transporter expression in patients with progressive disease compared to those with stable disease (chi 2 = 4.0, p < 0.05). Nucleoside transporter expression correlated significantly with the plasma cell labeling index (LI) (r = 0.45, p < 0.01) and serum thymidine kinase levels (r = 0.66, p < 0.01), both markers of cellular proliferation but not with c-myc oncoprotein expression. These findings suggest that flow cytometric measurement of nucleoside transporter expression on plasma cells provides a rapid and convenient measurement of disease activity or quiescence in myeloma.
Leuk Lymphoma 1994 May
PMID:Multiple myeloma: expression of nucleoside transporters on malignant plasma cells and their relationship to cellular proliferation. 806 94

We analysed diagnostic phase plasma levels of thymidine kinase (TK) and mutated p53 in 81 patients with malignant lymphoma. Forty-three (53%) patients had increased (> 10 U/l) TK activity whereas 30 (37%) were positive for the mutated p53 gene product. In general, patients with p53 mutation positive tumors tended to have higher TK activity than those without. Furthermore, patients with high-grade non-Hodgkin's lymphoma (NHL) showed almost a linear correlation (rs = 0.79) between plasma levels of mutated p53 and TK. We conclude that the monoclonal antibody assisted detection of mutated p53 gene product may prove a useful adjunct to the diagnostic procedures of malignant lymphomas.
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PMID:Evaluation of plasma levels of thymidine kinase and mutated p53 in 81 patients with newly diagnosed malignant lymphoma. 830 26

It has recently been suggested that a combination of C-Reactive Protein (CRP) and beta-2-microglobulin (beta 2M) can be used to devise a simple prognostic model for patients with multiple myeloma. In this study we have measured serum beta 2M, CRP and thymidine kinase (STK) in a series of 215 samples to determine their value as a monitor of disease status. A longitudinal study was also performed with 6 individual patients. CRP levels did not correlate with disease status. The mean of the stable (23.62 mg/L) and the progressive disease 23.64 mg/L) groups were almost identical (t = 0.003; p = NS) with ranges of < 5-150 mg/L and < 5-100 mg/L respectively. There was no correlation between CRP and STK (r = 0.11) or CRP and beta 2M (r = 0.05). In longitudinal studies, CRP did not necessarily reflect changes in disease activity. We conclude that CRP measurements are not valuable as a monitor of disease activity in patients with myeloma.
Leuk Lymphoma 1993 Apr
PMID:C-reactive protein (CRP) levels do not reflect disease status in patients with multiple myeloma. 833 52

Mutagenic lesions at the thymidine kinase locus (tk) in mouse lymphoma L5178Y (LY) cells treated with red light and either Photofrin (PF) or chloroaluminum phthalocyanine (AlPc) as the photosensitizer were compared in the relatively photodynamic therapy (PDT)-sensitive strain LY-R16 and the relatively resistant strains LY-S1 and LY-SR1. Southern blot analysis revealed that 92% (36/39) of the PDT-induced thymidine kinase (TK-/-) mutants of strains LY-R16 and LY-SR1 lost the entire active tk allele. (Strain LY-S1 lacks a known tk polymorphism and has not been analyzed for loss of the active tk allele.) A decrease in galactokinase (GK) activity in the TK-/- mutants has been taken as an indication that the mutagenic lesion extends from the tk gene to the closely linked galactokinase gene (gk). Using PF as the photosensitizer, GK activity was decreased in 45% of the LY-R16 mutants and in 22% of the LY-S1 and LY-SR1 mutants. With photoactivated AlPc, 59% of the TK-/- mutants of strains LY-S1 and LY-SR1 showed GK inactivation. (LY-R16 mutants were not analyzed because of the low LY-R16 mutant frequency induced by PDT with AlPc) Thus, many of the TK-/- mutants of LY cells induced by PDT with either PF or A1Pc harbor multilocus lesions.
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PMID:Large mutagenic lesions are induced by photodynamic therapy in murine L5178Y lymphoblasts. 841 19


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