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)

Antitumor effects of herpes simplex virus-thymidine kinase (HSV-tk) gene transfer followed by ganciclovir (GCV) administration were studied by serial magnetic resonance imaging (MRI) with reference to the bystander effect. Mixed populations of 9L-gliosarcoma cells transduced with the HSV-tk gene (TK cells) and wild-type 9L cells were implanted into the brain of syngeneic Fisher rats at various ratios (total cell number, 10(5) cells; percentage of TK cells, 100%, 25%, 10%, or 0%). Rats were treated with GCV (30 mg/kg per day) or saline for 14 days and tumor masses were visually monitored using MRI. All of the saline-treated rats (regardless of TK cell percentage) and GCV-treated rats inoculated with 0% TK cells died between day 19 and day 31 (mean survival, 22.9 days) due to progressive tumor growth. The GCV-treated rats inoculated with more than 10% of TK cells lived significantly longer than the saline-treated rats (p < 0.01). The mean survivals of GCV-treated groups were 50.7, 70.0, and longer than 100 days for 10%, 25%, and 100% TK cells, respectively. MRI study revealed that reduction in tumor size and disappearance of tumor were observed in the GCV-treated rats inoculated with 10% or 25% TK cells. Complete regression of the tumor was, however, observed only in the rats implanted with 100% TK cells. The present results show that the bystander effect is clearly observed in vivo in a TK percentage-dependent manner, and a population of more than 25% of TK-positive cells is required for complete tumor elimination.
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PMID:Evaluation of the bystander effect in experimental brain tumors bearing herpes simplex virus-thymidine kinase gene by serial magnetic resonance imaging. 889 76

The hemagglutinating virus of Japan (HVJ)-liposome method involves the entrapment of DNA and nuclear protein within liposomes and the use of HVJ to enhance liposome fusion with cell membranes. This method has been used successfully for in vivo gene transfer to various types of tissue. In this study, we investigated whether this method transfers genes effectively to normal and malignantly transformed keratinocytes in vivo. We applied HVJ-liposome complex (HLC) containing the beta-galactosidase gene to the tape-stripped skin of hairless rats and detected the enzyme activity in the keratinocytes of the treated skin. Comparison of this method with the naked DNA injection method, which was shown recently to be useful for in vivo gene transfer to keratinocytes, demonstrated that the transfer efficiency of the latter was about 5 times higher than that of the former. We assessed the efficacy of the HVJ-liposome method for gene transfer to transformed keratinocytes by examining the effect of HLC containing the herpes simplex virus thymidine kinase gene on the growth of mouse squamous cell carcinomas. Local injection of HLC into the tumors followed by administration of ganciclovir to mice resulted in tumor growth inhibition. These results indicate that the HVJ-liposome method is suitable for in vivo gene transfer to keratinocytes; also that this method may prove a good tool for basic research into keratinocyte biology and future keratinocyte gene therapy.
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PMID:In vivo transfer of a foreign gene to keratinocytes using the hemagglutinating virus of Japan-liposome method. 900 33

A new method of biochemical modulation of 5-fluorouracil (5-FU) with 3'-azido-3'-deoxythymidine (AZT) was studied experimentally. Nude mice transplanted with cells of the human gastric cancer cell line MKN28 were divided into 4 groups, i.e., control, 5-FU, AZT, and 5-FU plus AZT, and the antitumor activities were compared. Based on the assessment of tumor volume, significant suppression of tumor growth was observed in the 5-FU and 5-FU plus AZT groups (P<0.05, P<0.01, versus control, respectively). The thymidylate synthase (TS) inhibition rate, an index of inhibition of the de novo pathway, was significantly higher in the 5-FU and 5-FU plus AZT groups than in the control group (P<0.01), but it did not differ from the control in the AZT group. TS-bound FdUMP tended to be higher in the 5-FU plus AZT group than in the 5-FU group. The activity of thymidine kinase (TK) and the uptake ratio of 5-bromo-2'-deoxyuridine (BrdU), indices of salvage pathway activity, were significantly lower in the AZT and 5-FU plus AZT groups than in the control group (TK, P< 0.05, P < 0.01; uptake ratio of BrdU, P < 0.01, P < 0.05, respectively). There were slight losses of body weight in the 5-FU and 5-FU plus AZT groups compared with that in the control group, but no difference between the AZT and control groups in weight loss. These findings suggest that addition of AZT plays an important role in potentiating the antitumor activity of 5-FU through both blockage of a compensatory increase of activity in the salvage pathway and also an increase in TS-bound FdUMP, and has no adverse effects. Thus, the combination of 5-FU and AZT could be useful as a new modality in gastric cancer chemotherapy.
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PMID:Experimental studies on potentiation of the antitumor activity of 5-fluorouracil with 3'-azido-3'-deoxythymidine for the gastric cancer cell line MKN28 in vivo. 904 2

The "bystander effect" describes the killing of nearby unmodified cells and herpes simplex thymidine kinase (HTK)-transduced cells by ganciclovir (GCV) treatment. This effect is thought to be produced by contact between these cells. In this study, we showed that injected glioma cells migrated rapidly to a place distant from the injection point whereas injected virus-producing fibroblast cells did not migrate in a murine brain model. Moreover, the initially injected glioma cells and glioma cells injected at a later time mix very well, even at a place distant from the injection point. This suggested that glioma cells migrating after injection could be targeted by HTK-modified glioma cells introduced in a second injection and be killed together by GCV treatment. Therefore, we injected HTK-modified glioma cells 3 days after injection of wild glioma cells to investigate whether wild-type glioma cells that migrated to a place distant from the injection point could also be killed by GCV treatment. Tumor growth was suppressed after the GCV treatment. Suppression of tumor growth of wild glioma cells is not solely mediated by the immune response, which may be triggered by the killing of HTK-modified glioma cells with GCV, because inoculation of HTK-modified glioma to the contralateral side followed by GCV treatment did not cure the initial wild glioma. Moreover, the migration of the second inoculum of glioma cells is necessary for effective killing, because early administration of GCV resulted in insufficient killing.
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PMID:Targeted killing of migrating glioma cells by injection of HTK-modified glioma cells. 905 13

The carcinoembryonic antigen (CEA) is a glycoprotein which overexpressed in the majority of human gastric cancers. We demonstrated that recombinant adenoviral vector (AdCEAtk), containing the CEA promoter, could transfer the herpes simplex virus thymidine kinase (HSVtk) gene into CEA-producing gastric cancer cells to confer sensitivity to ganciclovir (GCV) in vivo. In an ex vivo experiment, the tumor growth was inhibited after GCV treatment when the tumor contained more than 20% of AdCEAtk infected cells, indicating an efficient bystander killing effect. With intra-tumoral injection of AdCEAtk, the HSVtk were selectively expressed in approximately 30% of CEA producing cancer cells. By AdCEAtk injection and GCV administration, the growth of tumors was significantly inhibited by 20% as compared to untreated tumors. It is hoped that these results provide a strategy of tumor specific gene transfer for CEA producing gastric cancers.
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PMID:Adenovirus-mediated gene therapy of gastric carcinoma using cancer-specific gene expression in vivo. 907 Aug 91

Replication-defective adenovirus vectors were generated in which the gene of interest (lacZ, luciferase or HSV-tk) is driven by the adenovirus major late promoter (MLP) or the human cytomegalovirus immediate-early gene promoter/enhancer (CMV). In vitro experiments with rat (II-45) and human (MERO 25) mesothelioma cell lines revealed that the CMV promoter was stronger than the MLP promoter regarding levels of expression of the luciferase reporter gene and ganciclovir (GCV) killing efficiency after tk gene transfer. Following administration of IG.Ad.CMV.lacZ recombinant adenovirus (Introgene, IG) into the pleural cavity of Fischer rats with established mesothelioma, a widespread distribution of infectious virus particles through the thorax contents was demonstrated. However, a relatively small proportion of tumor cells were transduced. Nevertheless, a strong tumor growth inhibition was observed following treatment with IG.Ad.CMV.TK recombinant adenovirus and GCV. Separate groups of rats inoculated on day 0 with 10(5) II-45 cells in the pleural cavity, received 7 x 10(9) infectious particles of IG.Ad. CMV.TK on day 1, day 2, day 4 or day 8. One day after virus administration, 25 mg/kg GCV or PBS (controls) was injected i.p. (intraperitoneally) twice daily. On day 15, all animals were killed. Significant tumor regression, equivalent to 5 log cell kill, occurred in the treated rats suggesting an impressive bystander effect. In a survival study, animals were treated 9 days after inoculation of 10(5) tumor cells with IG.Ad.CMV.TK and a 14 days course of GCV. This treatment prolonged symptom-free survival time from 19 days in the controls to 33 days in the treated group. These responses can be best explained by assuming continued tk expression in or around the tumor tissue during GCV treatment. Our results confirm and extend earlier findings with the same model and demonstrate the potential of the herpes simplex virus thymidine kinase suicide gene therapy as a local treatment for malignant mesothelioma.
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PMID:Gene therapy of experimental malignant mesothelioma using adenovirus vectors encoding the HSVtk gene. 917 12

We examined a possible antitumor response against 9L rat gliosarcoma cells induced by the expression of the herpes simplex virus-thymidine kinase (HSV-TK) gene and the ganciclovir (GCV) system. Based on the amount of the major histocompatibility complex (MHC) class I antigens expressed on 9L cells transduced by the HSV-TK gene (9L/HSV-TK) we selected two clones (clones H and L), which represent high and low expressors of class I antigens, respectively. By means of serial magnetic resonance imaging we followed the change of tumor volumes of each clone in syngeneic rats, and found that the intracranial tumor growth was inversely correlated with the expression of MHC class I antigens, although in vitro growths of the clones remained unchanged. Moreover, histological examination revealed significant lymphocyte infiltration in the 9L/HSV-TK tumor of high MHC expression but not in the wild-type tumor. The therapeutic effect of GCV on them was not different, but we observed a prolonged survival of the rats which had eliminated 9L/HSV-TK clone L tumors by the treatment of GCV and were rechallenged with the same cells compared with the survival of naive rats inoculated with clone L cells. These data collectively suggest that the immune response operates even in the brain previously described as an immunologically privileged site.
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PMID:Induction of acquired immunity in rats that have eliminated intracranial gliosarcoma cells by the expression of herpes simplex virus-thymidine kinase gene and ganciclovir administration. 921 59

To investigate the potential of the thymidine kinase gene from Varicella zoster virus (VZVtk) to act as a suicide gene, VZVtk was transferred via a dicistronic retroviral construct into MCF7, T-47D and MDA-MB-435 human breast cancer cells. The cytotoxicity of antiviral drugs was then evaluated in vitro on the wild-type and transduced cells. Acyclovir and ganciclovir did not show any selective toxicity for the modified cells. In contrast, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was extremely toxic for the VZVtk expressing cells, with IC50 values of 0.6 microM, 0.1 microM and 0.06 microM for MCF7, T-47D and MDA-MB-435 cells, respectively. The selectivity index of BVDU (ie the IC50 value ratio of the wild-type to the VZVtk cells) was 400 for MCF7, 750 for T-47D and 2000 for MDA-MB-435 cells. To test the system in vivo, VZVtk carrying MDA-MB-435 cells were inoculated subcutaneously into nude mice. An intraperitoneal treatment with BVDU administered at the emergence of the tumors, led to a prolonged arrest of the tumor growth and a reduced tumor mass. This effect was BVDU dose-dependent. No bystander effect of BVDU killing could be demonstrated in vitro on mixed populations of VZVtk positive and negative MDA-MB-435 cells. However, an important bystander effect was observed in identical experiments performed on 9L rat gliosarcoma cells infected with the VZVtk-carrying vector. These results demonstrate the efficiency of VZVtk as a suicide gene when BVDU is used as prodrug. The bystander effect measured in vitro, depends however on the tumoral cell type used.
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PMID:Potential of Varicella zoster virus thymidine kinase as a suicide gene in breast cancer cells. 923 Oct 72

To elucidate the role gap junctions play in the bystander effect, we examined the cytotoxic effect of herpes simplex virus thymidine kinase (HSVtk) modified tumor cells on gap junction communication-deficient tumor cells and their connexin transfectants. Communication competent Walker 256 tumor cells engineered to express the HSVtk gene (Walker-tk+) when cocultured with N2A mouse neuroblastoma and PC12 rat pheochromocytoma cells with absent endogenous junctional conductance showed no bystander cytotoxicity. Transfection of N2A cells with the rat connexin37 gene (5Q) and PC12 cells with the human connexin43 gene rendered them susceptible to bystander cell death. Additionally, communication-deficient N2A cells transfected with the HSVtk gene failed to exert a bystander effect, whereas N2A transfectants coexpressing the connexin37 and HSVtk genes (5Qtk+ cells) exerted bystander cytotoxicity on gap junction communication-competent 5Q but not on communication-deficient N2A cells in vitro. In vivo experiments also showed tumor growth inhibition of communication-competent 5Q but not communication-incompetent N2A cells by 5Qtk+ cells. In conclusion, these results indicate that in several cellular environments the bystander effect is dependent on connexin expression and gap junctional communication between HSVtk-positive and HSVtk-negative cells.
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PMID:The bystander effect exerted by tumor cells expressing the herpes simplex virus thymidine kinase (HSVtk) gene is dependent on connexin expression and cell communication via gap junctions. 923 Oct 74

The growth of U-87 or C6 gliomas co-implanted in nude mice with retroviral producer cells (VPC) expressing the herpes simplex virus-thymidine kinase (HSV-tk) gene is only partially impaired by treatment with ganciclovir (GCV). The effect of GCV is even less evident when C6 and VPC are co-implanted into the rat brain. Furthermore, tumors from C6 cells carrying the HSV-tk gene are not eradicated by GCV, although they remain sensitive to GCV when replated in vitro. These limits of the HSV-tk/GCV system in glioma gene therapy may be due to insufficient gene transfer and/or insufficient delivery of GCV to glioma cells. Combination of HSV-tk and one or more cytokines may improve the antitumor efficacy. Among cytokines, interleukin-4 (IL-4) has already been shown to be active against gliomas. In nude mice, GCV treatment inhibited tumor growth more effectively after co-injection of C6 cells with a mixture of VPC transducing IL-4 and HSV-tk genes than after co-injection with either IL-4 or HSV-tk VPC only. In immunocompetent Sprague-Dawley rats, co-injection of IL-4 VPC and C6 cells was also effective in inhibiting the growth of C6 brain tumors, 38% of the animals surviving for at least 2 months. Furthermore, increased and prolonged antitumor efficacy was obtained by transducing both IL-4 and HSV-tk genes.
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PMID:Limited efficacy of the HSV-TK/GCV system for gene therapy of malignant gliomas and perspectives for the combined transduction of the interleukin-4 gene. 929 29


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