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)

A 6.2-fold cis-diamminedichloroplatinum(II) (CDDP) resistant human lung cancer cell line (A549/CDDP5), which was capable of proliferating in the presence of 5 microM CDDP, was developed. Compared to the parent cell line, A549/CDDP5 subline had a significantly longer doubling time, increased population of S phase, enhanced sensitivity to 5-FU and elevated activities of dTMP synthase (EC 2.1.1.45) and thymidine kinase (EC 2.7.1.21) by 5.4- and 2.0-fold of the parent cells. These results suggest that the capacity of dTMP synthesis might have an important role in the acquisition of CDDP resistance of A549 cells.
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PMID:Establishment and biochemical properties of cis-diamminedichloroplatinum(II)-resistant A549 lung cancer cells. 184 10

Compared to either compound alone, the combination of acivicin and cis-diamminedichloroplatinum(II) markedly enhanced the inhibition of the activities of thymidylate synthase and thymidine kinase, the enzymes involved in the final steps of the de novo and salvage pathways in pyrimidine metabolism in A549 lung cancer cells. The enhancement of enzymic inhibition paralleled that of cell growth inhibition. These results indicate that the combination of these drugs can inhibit the capacities of the pyrimidine pathways, resulting in an efficient reduction of DNA synthesis.
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PMID:Effects of the combination of acivicin and cis-diamminedichloroplatinum(II) on thymidylate synthesis of A549 lung cancer cells. 273 Jun 61

A human primary lung carcinoma cell line (HPL-R1) established from the tumor biopsy of a lung cancer patient, lacking in cytochrome P1-450 [aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH)], was cloned and used to obtain variants deficient in the expression of thymidine-kinase via treatment with 5-bromo-2'-deoxyuridine, and selection for drug resistance phenotype. The variant cell line, precharacterized for thymidine kinase negative phenotype, was transfected with the thymidine kinase gene bearing p R-tk and px1-tk plasmids. Transfections from both the plasmids, demonstrated a frequency of 5.5 X 10(-5). The transfectants showed a 76-100% retention of the transferred phenotype. These data suggest that transfection in variant human cells can approach significant levels of stability observed with rodent cell recipients.
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PMID:Plasmid DNA mediated transfer of the herpes simplex virus thymidine kinase gene to a new bromodeoxyuridine resistant variant of human primary lung carcinoma cells. 283 65

An improved method for the detection of deoxythymidine kinase (TK) in human sera is reported. The method which utilizes 125I-iododeoxyuridine (IdUrd) as a substrate was used to measure TK in sera from patients with different diseases. Sera collected during the acute stage of infectious mononucleosis were found to contain elevated levels of TK, in most cases 10-40 times the normal value. The serum TK activity disappeared gradually and reached a normal level within 4 weeks. Sera from patients with other viral infections contained in most cases normal serum TK levels except in connection with measles, rubella, varicella, herpes simplex virus and cytomegalovirus infections. Additional studies revealed that sera from patients with different types of advanced lymphomas, acute leukemias, chronic granulocytic leukemia and lung cancer of the small-cell type with metastases, contained high TK levels which fluctuated in parallel with alterations in activity of the disease. The TK activity in sera from patients with both mononucleosis and tumor disease was characterized by electrophoresis and by its ability to utilize cytidine triphosphate as the phosphate donor. The results showed that the serum TK has the same properties as the human cytosolar TKI, except in connection with varicella.
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PMID:Application of an in vitro assay for serum thymidine kinase: results on viral disease and malignancies in humans. 669 95

Previous studies have shown adenoviral transfer of the herpes simplex virus thymidine kinase (HSVtk) gene followed by the anti-viral drug ganciclovir (GCV) can be used to successfully treat established human mesothelioma tumors growing within the peritoneal cavities of severe combined immune deficient (SCID) mice. These findings raised a number of questions important to the applicability, efficiency, and safety of this treatment strategy. In this report, we have further characterized the use of recombinant adenovirus carrying the HSVtk gene to treat mesothelioma and other localized malignancies. Our results indicate that the Ad.RSVtk/GCV system is effective in causing tumor regression in animals inoculated with another mesothelioma cell line and a lung cancer cell line and that animals with bulky disease can be successfully treated. Effects are seen at a wide range of virus doses and significant anti-tumor activity is present at doses of ganciclovir that are clinically achievable. Finally, this treatment approach appears safe, with limited dissemination of virus using a sensitive RT-PCR detection system. These studies further characterize the use of adenoviral transfer of the HSVtk gene to treat experimental mesothelioma and suggest that clinical trials using this approach may be feasible.
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PMID:Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer. 759 39

We used a recombinant retrovirus as one of the potential vectors for human gene therapy to transfer a drug sensitivity gene into human lung cancer cells. The gene encoding the thymidine kinase (TK) of herpes simplex virus type 1 (HSV1) was used as the drug sensitivity gene. The antiherpes drugs acyclovir (ACV) and ganciclovir (GCV) were chosen to test the HSV1-TK activity transferred into the human lung cancer cell lines. The rationale for this approach was that ACV and GCV are nucleoside analogs specifically converted by HSV1-TK to a toxic form capable of inhibiting DNA synthesis or disrupting cellular DNA replication. The results obtained from our experiments demonstrate that the retroviral vector-mediated HSV1-TK gene transfer leads to ACV- and GCV-dependent cytotoxicity in human lung cancer cell lines, including both small-cell carcinoma and non-small-cell carcinoma. Although the gene transfer of HSV1-TK gene into tumor cells would be one model for gene therapy to control lung cancer, further investigations are necessary for the proper choice of the therapeutic gene and vector targeting such as tumor cell specific delivery of the gene or tumor cell specific expression of the transduced gene.
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PMID:Retroviral transfer of HSV1-TK gene into human lung cancer cell line. 763 46

A carcinoembryonic antigen (CEA)-producing human lung cancer cell line (A549), a nonproducing human lung cancer cell line (CADO-LC9), and a human uterine cervical cancer (HeLa) were transfected with the herpes simplex virus thymidine kinase (HSV-TK) gene regulated by 445 nucleotides upstream from the translational start of CEA gene. Fifty % growth inhibitory concentration of ganciclovir (GCV) was 0.57 micron for HSV-TK-transfected A549; relative sensitivity to GCV was more than 1000 times higher compared to the 50% growth inhibitory concentration of the parental cell line. Both CADO-LC9 and HeLa transfected with HSV-TK were still resistant to GCV. There was no difference in either morphology or doubling time between HSV-TK-transfected and parental clones. Injections (i.p.) of GCV resulted in significant regression of HSV-TK-transfected A549 tumors in nude mice. These data show the possibility of gene therapy using the cell type-specific promoter of CEA gene against CEA-producing adenocarcinoma of the lung.
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PMID:Gene therapy for carcinoembryonic antigen-producing human lung cancer cells by cell type-specific expression of herpes simplex virus thymidine kinase gene. 792 50

In order to investigate the usefulness of thymidine kinase, which acts to salvage thymidine to its nucleotide for DNA biosynthesis, as a marker of malignancy in lung cancer, the enzyme activities in extracts of tumors and uninvolved lungs of 83 resected cases of lung cancer were determined. The mean value of thymidine kinase activity in tumors was as much as 4.3 times higher than that of uninvolved lungs. There was no significant correlation between the activity in tumors and clinicopathological findings such as histological type, the grade of histological differentiation, pT factor, pN factor, pTNM stage and tumor size. The tumor doubling time did, however, show a significant inverse correlation with activity when compared logarithmically (r = 0.879, p = 0.00002). Moreover, there was a significant relationship between enzyme activity and post-operative recurrence of lung cancer. In conclusion, thymidine kinase was found to be a useful marker of malignancy in lung cancer.
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PMID:[A study of thymidine kinase activity in lung cancer tissue]. 818 40

One of the recent strategies for gene therapy as a cancer control is the targeted introduction of a drug-sensitivity gene into tumor cells. We investigated the gene transfer of herpes simplex virus type I thymidine kinase (HSV-TK) gene as a drug-sensitivity gene into human lung cancer cell lines. We used a recombinant retroviral vector derived from Moloney murine leukemia virus (MuLV) as one of potential vectors for gene therapy. The amphotropic retroviral vector consisted of the HSV-TK gene and the neomycin-resistant gene under Rous sarcoma virus (RSV) promoter control. The antiherpes drugs, acyclovir (ACV) and ganciclovir (GCV), were chosen for testing the activity of HSV-TK that was transferred into human lung cancer cell lines. ACV and GCV are nucleoside analogs specifically converted by HSV-TK to a toxic form capable of inhibiting DNA synthesis. The cytotoxicity was determined by using a tetrazolium-based colorimetric assay (MTT assay). The results obtained from our experiments demonstrated that the retroviral vector-mediated HSV-TK gene transfer leads to ACV- and GCV-dependent cytotoxicity in human lung cancer cell lines, which were both small cell carcinoma and non-small cell carcinoma established from human specimens. These findings suggest that the gene transfer of HSV-TK gene into tumor cells would be one of the models for the use of gene therapy to control lung cancer.
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PMID:Gene transfer of herpes simplex virus type I thymidine kinase gene as a drug sensitivity gene into human lung cancer cell lines using retroviral vectors. 839 27

Lung cancer is a leading cause of cancer death and standard chemotherapies are resulting in only marginal improvements in outcome. Experimental approaches involving gene therapy are attractive in this clinical setting. There are two basic types of genes utilized, either those intended to induce immunity or those that are directly tumoricidal. Immunity-inducing genes that have been used in model (and some human) systems include MHC molecules, costimulatory molecules, and cytokines such as IL-2, IL-4, IL-6, GM-CSF. These are intended to induce effective systemic immune responses against tumor antigens which would not otherwise develop. Direct toxic approaches include the reintroduction of tumor suppressor genes or enzymes which convert non-toxic drugs to toxic ones, such as herpes thymidine kinase. As a means for gene delivery, retroviruses are the most common vehicle, although Adenovirus vectors and direct DNA delivery have specific advantages.
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PMID:Gene therapy for lung cancer. 861 19


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