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:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanin biosynthesis is limited to melanocytes partly as a consequence of transcriptional regulation of the enzymes involved in this pathway. Promoter sequences of these enzyme genes may be utilised to drive expression of complementary DNA coding for therapeutic genes so as to provide transcriptional targeting. We have used the 5'-flanking sequences of the murine tyrosinase or tyrosinase-related protein 1 (TRP-1) genes to show that such transcriptional targeting can be achieved both in vitro and in vivo. Using IL-2 as an example of an immunostimulatory gene and Herpes Simplex Virus thymidine kinase (HSVtk) as an example of a prodrug-activating gene we have shown, in murine model systems, that substantial anti-tumour effects can be achieved by targeted gene therapy approaches. The stage now is set for initial clinical evaluations in human patients.
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PMID:Targeted gene therapy. 755 86

To target therapeutic genes specifically to melanoma cells, we have constructed recombinant retroviruses where transcriptional control of the murine interleukin-2 (mIL-2) or herpes simplex virus thymidine kinase (HSVtk) genes is provided by the 5' promoter region of the murine tyrosinase gene. Tissue-specific expression of these genes is observed both at the mRNA and protein levels in the B16 melanoma line compared with NIH3T3 fibroblasts. Thus, B16 cells infected with one such retrovirus containing the HSVtk gene exhibited a > 90% reduction in colony-forming efficiency after exposure to 1 microgram/ml ganciclovir, relative to controls, whereas similarly infected NIH3T3 cells showed < 10% reduction in colony-forming efficiency under comparable conditions. The degree of preservation of tissue-specific expression from the internal tyrosinase promoter depended upon the exact molecular design of the vector, possibly as a consequence of the interference between closely juxtaposed promoters within the provirus. Our results show that retroviral vectors can be prepared with the capacity to regulate expression of inserted genes specifically in a particular cell type and may be useful for developing efficient, targeted vectors for the in vivo delivery of genetic therapies for malignant melanoma.
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PMID:A comparison of the properties of different retroviral vectors containing the murine tyrosinase promoter to achieve transcriptionally targeted expression of the HSVtk or IL-2 genes. 758 96

We report here the use of the 5' flanking region of the murine tyrosinase gene to direct expression of the herpes simplex virus thymidine kinase (tk) gene specifically to murine melanoma cells, whilst not permitting expression in a range of other cell types. Expression of the herpes simplex virus tk gene from the tyrosinase promoter in melanoma cells rendered them sensitive to killing by ganciclovir (100% cell death of a tk-expressing B16 clone after 12 days in culture at 1 microgram/ml ganciclovir). We also observed a substantial bystander killing effect when expressing cells were mixed with nontransfected parental B16 cells. When transfected murine melanoma cells expressing tk were injected into syngeneic mice both their tumorigenicity and experimental metastatic potential were abrogated completely when the mice were treated with ganciclovir (27 of 28 mice treated with water developed progressively growing tumors versus 1 of 30 in the ganciclovir-treated group). Direct injection of the tk gene under control of the tyrosinase promoter into established tumors in mice, followed by treatment with ganciclovir, led to significant reductions in resultant tumor size relative to the size of tumor developing in mice treated with water (median tumor weight, 1.65 g versus 2.75 g). Therefore, direct transfer of recombinant genes by injection of DNA can significantly reduce established tumor burden in vivo.
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PMID:Use of tissue-specific expression of the herpes simplex virus thymidine kinase gene to inhibit growth of established murine melanomas following direct intratumoral injection of DNA. 839 31

Melanin biosynthesis is restricted to melanocytes partly as a consequence of transcriptional regulation of the mRNA coding for those enzymes involved in this biochemical pathway. Promoter sequences of these genes may be used to regulate expression of complementary DNA coding for therapeutic genes so as to provide transcriptional targeting. As a model system we have used the 5'-flanking sequences of the murine tyrosinase or tyrosinase-related protein 1 (TRP-1) genes to show that such transcriptional targeting can be accomplished both in vitro and in vivo. Using interleukin-2 (IL-2) as an example of an immunostimulatory gene and herpes simplex virus thymidine kinase (HSVTK), as an example of a prodrug-activating gene we have shown, in murine model systems, that marked antitumour effects can be achieved by targeted gene therapy approaches. Because other tumor types produce particular proteins as a consequence of specific transcription it is possible that this approach may provide a way of targeting therapeutic genes to various cancers.
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PMID:Tissue specific promoters in targeting systemically delivered gene therapy. 860 25

The ability to specifically and efficiently express selected genes in tumor cells is an important goal for cancer gene therapy. Transcriptional targeting of adenovirus to tumor cells, thereby limiting their expression to specific cell types, represents one experimental approach to this problem. We have previously shown that a recombinant adenovirus containing the murine tyrosinase promoter coupled to a dimer of the tyrosinase-enhancer element can target the expression of beta-galactosidase cDNA to melanoma cells. We now report that this same promoter/enhancer cassette can efficiently drive the expression of the herpes simplex virus thymidine kinase gene in melanoma cells. Infection of melanoma cells with the AdmTyr-tk virus along with subsequent ganciclovir treatment induces S phase cell cycle arrest associated with a profound change in cell size and morphology. Treated cells remain viable for prolonged periods, but clonogenic assays demonstrate that the cell cycle arrest is irreversible. In contrast, nonmelanoma cells are unaffected by this treatment regimen, exhibiting normal growth kinetics, metabolic activity, and cell cycle progression. The therapeutic efficacy of the AdmTyr-tk virus was tested in vivo using a xenograft model of human melanoma. The injection of the AdmTyr-tk virus into established subcutaneous tumor nodules in combination with systemic ganciclovir administration led to a decreased tumor growth rate and to complete tumor regressions in some cases. These studies demonstrate the feasibility of selectively targeting growth-inhibitory genes to melanoma cells in vitro and in vivo.
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PMID:Melanoma-specific cytotoxicity induced by a tyrosinase promoter-enhancer/herpes simplex virus thymidine kinase adenovirus. 982 47

The purpose of this study was to investigate the regulation of tyrosinase gene expression and activity in cultured human retinal pigment epithelial (RPE) cells. The tyrosinase promoter (Ty.prom) region (400 bp) was PCR amplified and cloned into a modified mammalian expression vector (pcDNA3.1) upstream of a firefly luciferase (Luc) cDNA and was designated 'pcDNA3.1-Ty.prom.Luc'. The plasmid was co-transfected into RPE cells with a second mammalian expression plasmid (pRL-TK) containing a herpes simplex virus thymidine kinase promoter region upstream of Renilla Luc in a protocol designated the 'dual luciferase assay' (DLA). After co-transfection, cells were treated with a range of potential melanogenic agents; basic fibroblast growth factor (bFGF), methyl methane sulphonate, alpha-melanocyte stimulating hormone, verapamil, phorbol myristate acetate, cholera toxin (CT), pigment epithelium derived factor (PEDF), and L-tyrosine. The expression of tyrosinase promoter and enzymatic activities were determined 48 hr post-transfection using the DLA and DOPA oxidase assays, respectively. Tyrosinase activity could not be detected in RPE cells with any of the treatments. Tyrosinase promoter activity was significantly up-regulated in RPE cells treated with bFGF, PEDF, verapamil, CT and tyrosine compared with control cells. In conclusion, the tyrosinase gene is not only expressed but can be regulated in response to different chemicals in cultured human RPE cells. However, it appears that RPE cells in culture lack a post-transcriptional and/or translational modification point(s), which are necessary for tyrosinase enzymic activity.
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PMID:Regulation of tyrosinase expression and activity in cultured human retinal pigment epithelial cells. 1115 95

Selective killing of tumors can be achieved by targeting the transcription of suicide genes via specific DNA control elements to malignant cells. Three different enhancer-promoter systems were constructed and evaluated for their capability to direct gene expression to melanoma. Two tissue-specific (tyrosine and MIA) promoters and one weak viral promoter were fused to multiple tandem copies of a melanocyte-specific enhancer element. Reporter gene assays revealed a maximum increase in transcription by combining each promoter with 3-4 copies of the enhancer and demonstrated that all enhancer-promoter combinations exhibited tissue-specific activity. Though this activity was still significantly less than that of the strong but unspecific cytomegalovirus (CMV) promoter. In contrast, when those combinations were employed to drive the expression of two suicide genes, encoding the diptheria toxin A chain (DT-A) and the prodrug-activating herpes simplex virus thymidine kinase (TK), respectively, only those constructs in which transcription was under control of tissue-specific promoter elements mediated selective killing of melanoma cells. This killing was in the range of cell death induced by CMV promoter activity. Our data indicate that the enhancer/tyrosinase and enhancer/MIA promoter constructs but not the viral promoter constructs can provide a valuable tool for selective suicide gene expression in melanoma.
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PMID:Evaluation of combined gene regulatory elements for transcriptional targeting of suicide gene expression to malignant melanoma. 1471 61

Historically, in vivo imaging methods have largely relied on imaging gross anatomy. More recently it has become possible to depict biological processes at the cellular and molecular level. These new research methods use magnetic resonance imaging (MRI), positron emission tomography (PET), near-infrared optical imaging, scintigraphy, and autoradiography in vivo and in vitro. Of primary interest is the development of methods using MRI and PET with which the progress of gene therapy in glioblastoma (herpes simplex virus-thymidine kinase) and Parkinson's disease can be monitored and graphically displayed. The distribution of serotonin receptors in the human brain and the duration of serotonin-receptor antagonist binding can be assessed by PET. With PET, it is possible to localize neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. MR tracking of transplanted oligodendrocyte progenitors is feasible for determining the extent of remyelinization in myelin-deficient rats. Stroke therapy in adult rats with subventricular zone cells can be monitored by MRI. Transgene expression (beta-galactosidase, tyrosinase, engineered transferrin receptor) can also be visualized using MRI. Macrophages can be marked with certain iron-containing contrast agents which, through accumulation at the margins of glioblastomas, ameliorate the visual demarcation in MRI. The use of near-infrared optical imaging techniques to visualize matrix-metalloproteinases and cathepsin B can improve the assessment of tumor aggressiveness and angiogenesis-inhibitory therapy. Apoptosis could be detected using near-infrared optical imaging representation of caspase 3 activity and annexin B. This review demonstrates the need for neurohistological research if further progress is to be made in the emerging but burgeoning field of molecular imaging.
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PMID:Molecular imaging: Bridging the gap between neuroradiology and neurohistology. 1502 22

Since RGD fiber-mutant adenovirus vector (AdRGD), which contains an alphav-integrin tropism, is highly efficient in gene transduction to melanoma, the AdRGD-mediated herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system is an attractive approach for melanoma treatment. However, the intratumoral injection of AdRGD causes limited transgene expression in healthy normal tissue, due to unwanted vector spread. Herein, we describe our attempt to overcome this limitation related to the safety of HSVtk/GCV treatment by using AdRGD carrying either melanoma-specific tyrosinase (Tyr) promoter or tumor-specific telomerase reverse transcriptase (TERT) promoter instead of universal cytomegalovirus promoter. Our in vitro study revealed that Tyr promoter-regulated AdRGD exhibited high transgene expression specificity for melanoma cells, and that TERT promoter-regulated AdRGD could induce efficient gene expression in tumor cells, but was relatively quiescent in normal cells. Anti-B16BL6 melanoma effects in mice injected intratumorally with AdRGD-Tyr/HSVtk or AdRGD-TERT/HSVtk, after which GCV was injected intraperitoneally for 10 days, were comparable to those in mice injected with AdRGD-CMV/HSVtk at 10 times less vector dosage. On the other hand, AdRGD-Tyr/HSVtk and AdRGD-TERT/HSVtk did not induce severe adverse effects even when they were intravenously injected into mice at 10(9) plaque-forming units (PFU), whereas mice injected with AdRGD-CMV/HSVtk at 10(8) PFU exhibited body weight reduction and serum level increase of biochemical enzymes for hepatotoxicity. These results indicate that AdRGD combined with transcriptional regulation using Tyr or TERT promoter is a potentially useful and safe vector system for suicide gene therapy for melanoma.
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PMID:Transcriptional targeting of RGD fiber-mutant adenovirus vectors can improve the safety of suicide gene therapy for murine melanoma. 1574 44

In preparation of the therapeutic genetic constructs aimed to the gene-programmed enzymatic transformation of the non-toxic prodrug into toxin within cancer cells the right choice of regulatory elements (promoters and enhancers) is essential. This is widely accepted that the efficiency of the gene therapy constructions is dependent, in particular, on the strength of promoters driving the expression of the therapeutic genes. In this work we demonstrated, using the melanoma-specific promoters and enhancers of human melanoma inhibitory activity and mouse tyrosinase gene, that for the development of cytotoxic effect the promoter strength is not of primary importance. In the case of HSVtk, coding for the herpes simplex virus thymidine kinase, and FCU1, coding for cytosine deaminase/uracil phosphoribosyltransferase hybrid protein genes, their cytotoxic activity was determined by the quantity of the added prodrug.
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PMID:[Cytotoxicity of cytosine deaminase and herpes simplex virus thymidine kinase genes in melanoma cells is independent on promoter strength]. 2569 36


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