Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular gene transfer may be useful for the treatment of several cardiovascular diseases. It can also be used as an experimental tool to test the effects of various genes in a local vascular compartment. Promising therapeutic effects have been obtained in animal models of restenosis with the transfer of vascular endothelial growth factor, nitric oxide synthase, thymidine kinase, retinoblastoma, growth arrest homeobox gene, cyclin/cyclin-dependent kinase inhibitor (p21), and hirudin genes, and antisense oligonucleotides against transcription factors or cell cycle regulatory proteins. Vascular endothelial growth factor and fibroblast growth factor gene transfers have improved blood flow and capillary development in models of ischaemic limb and myocardium. First experiences of vascular endothelial growth factor gene transfer to human peripheral arteries have also been reported. However, further developments in gene delivery techniques and gene transfer vectors will be required before a full therapeutic potential of gene therapy in cardiovascular diseases can be evaluated.
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PMID:Vascular gene transfer. 918 44

The mammalian homeobox gene pdx-1 is expressed in pluripotent precursor cells in the dorsal and ventral pancreatic bud and duodenal endoderm, which will produce the pancreas and the rostral duodenum. In the adult, pdr-1 is expressed principally within insulin-secreting pancreatic islet beta cells and cells of the duodenal epithelium. Our objective in this study was to localize sequences within the mouse pdx-1 gene mediating selective expression within the islet. Studies of transgenic mice in which a genomic fragment of the mouse pdx-1 gene from kb -4.5 to +8.2 was used to drive a beta-galactosidase reporter showed that the control sequences sufficient for appropriate developmental and adult specific expression were contained within this region. Three nuclease-hypersensitive sites, located between bp -2560 and -1880 (site 1), bp -1330 and -800 (site 2), and bp -260 and +180 (site 3), were identified within the 5'-flanking region of the endogenous pdx-1 gene. Pancreatic beta-cell-specific expression was shown to be controlled by sequences within site 1 from an analysis of the expression pattern of various pdr-1-herpes simplex virus thymidine kinase promoter expression constructs in transfected beta-cell and non-beta-cell lines. Furthermore, we also established that this region was important in vivo by demonstrating that expression from a site 1-driven beta-galactosidase reporter construct was directed to islet beta-cells in transgenic mice. The activity of the site 1-driven constructs was reduced substantially in beta-cell lines by mutating a hepatocyte nuclear factor 3 (HNF3)-like site located between nucleotides -2007 and -1996. Gel shift analysis indicated that HNF3beta present in islet beta cells binds to this element. Immunohistochemical studies revealed that HNF3beta was present within the nuclei of almost all islet beta cells and subsets of pancreatic acinar cells. Together, these results suggest that HNF3beta, a key regulator of endodermal cell lineage development, plays an essential role in the cell-type-specific transcription of the pdx-1 gene in the pancreas.
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PMID:Hepatocyte nuclear factor 3beta is involved in pancreatic beta-cell-specific transcription of the pdx-1 gene. 931 59

Vascular gene transfer offers a promising alternative for the treatment of cardiovascular diseases. Blood vessels are among the easiest targets for gene therapy and in most conditions only a temporary expression of the transfected gene will be required to achieve a beneficial biological effect. Adenoviruses lead to most efficient transgene expression in arterial wall. Depending on the treatment requirements, gene transfer to the artery wall can be accomplished both from lumen and from adventitia. Promising therapeutic effects have been obtained in animal models of restenosis with the transfer of vascular endothelial growth factor (VEGF), nitric oxide synthase, thymidine kinase, retinoblastoma, growth arrest homeobox gene and antisense oligonucleotides against transcription factors or cell cycle regulatory proteins. First experiences of VEGF gene transfer to human peripheral arteries have also been reported. However, further studies regarding gene transfer techniques, vectors and safety of the procedures are needed before a full therapeutic potential of gene therapy in vascular diseases can be evaluated.
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PMID:Adventitial gene transfer to arterial wall. 963 39

Local gene transfer into the vascular wall offers a promising alternative to treat atherosclerosis-related diseases at cellular and molecular levels. Blood vessels are among the easiest targets for gene therapy because of novel percutaneous, catheter-based treatment methods. On the other hand, gene transfer to the artery wall can also be accomplished from adventitia, and in some situations intramuscular gene delivery is also a possibility. In most conditions, such as postangioplasty restenosis, only a temporary expression of the transfected gene will be required. Promising therapeutic effects have been obtained in animal models of restenosis with the transfer of genes for vascular endothelial growth factor, fibroblast growth factor, thymidine kinase, p53, bcl-x, nitric oxide synthase and retinoblastoma. Also, growth arrest homeobox gene and antisense oligonucleotides against transcription factors or cell cycle regulatory proteins have produced beneficial therapeutic effects. Angiogenesis is an emerging new target for gene therapy of ischemic diseases. In addition, hyperlipoproteinemias may be improved by transferring functional lipoprotein-receptor genes into hepatocytes of affected individuals. First experiences of gene transfer methods in the human vascular system have been reported. However, further studies regarding gene delivery methods, vectors and safety of the procedures are needed before a full therapeutic potential of gene therapy in vascular diseases can be evaluated.
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PMID:Vascular gene transfer for the treatment of restenosis and atherosclerosis. 981 1

The caudal homeobox gene Cdx-2 is a transcriptional activator for approximately a dozen genes specifically expressed in pancreatic islets and intestinal cells. It is also involved in preventing the development of colorectal tumors. Studies using "knockout" approaches demonstrated that Cdx-2 is haplo-insufficient in certain tissues including the intestines but not the pancreatic islets. The mechanisms, especially transcription factors, which regulate Cdx-2 expression, are virtually unknown. We found previously that Cdx-2 expression could be autoregulated in a cell type-specific manner. In this study, we located an octamer (OCT) binding site within the mouse Cdx-2 gene promoter. This site, designated as Cdx-2(P)OCT, is involved in the expression of the Cdx-2 promoter. Both pancreatic and intestinal cell lines were found to express a number of POU (OCT binding) homeodomain proteins examined by electrophoretic mobility shift assay. However, it appears that Cdx-2(P)OCT interacts only with OCT1 in the nuclear extracts of the intestinal cell lines examined, although it interacts with OCT1 and at least two other POU proteins that are to be identified in the pancreatic InR1-G9 cell nuclear extract. Co-transfecting OCT1 cDNA but not five other POU gene cDNAs activates the Cdx-2 promoter in the pancreatic InR1-G9 and the intestinal Caco-2 cell lines. In contrast, Cdx-2(P)OCT cannot act as an enhancer element if it is fused to a thymidine kinase promoter. Furthermore, Cdx-2(P)OCT-thymidine kinase fusion promoters cannot be activated by OCT1 co-transfection. Cell type-specific expression, cell type-specific binding affinity of POU proteins to the cis-element Cdx-2(P)OCT, and the DNA content-dependent activation of Cdx-2 promoter via Cdx-2(P)OCT by OCT1 suggest that POU proteins play important and complicated roles in modulating Cdx-2 expression in cell type-specific manners.
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PMID:Pou homeodomain protein OCT1 is implicated in the expression of the caudal-related homeobox gene Cdx-2. 1127

Owing to the easy accessibility and general importance of the vascular system, cardiovascular diseases, including postangioplasty and graft restenosis, have become one of the new areas for gene therapy and molecular medicine. Promising therapeutic effects have been obtained in animal models of vascular diseases and restenosis with the transfer of genes for vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), thymidine kinase, p53, retinoblastoma, bcl-x, tissue inhibitor of metalloproteinase (TIMP), hepatic growth factor (HGF) and nitric oxide synthase (NOS). Also, growth arrest homeobox gene and antisense oligonucleotides or antibodies against transcription factors or cell cycle regulatory proteins have produced beneficial therapeutic effects. However, further developments in gene delivery techniques and vectors are needed before the full therapeutic effects of gene therapy in vascular diseases can be obtained.
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PMID:Gene therapy for the treatment of peripheral vascular disease and coronary artery disease. 1284 66

The formation of a normal pancreas and the activation of insulin production are, in part, dependent on the expression and activation of the pancreatic duodenal homeobox gene 1 (PDX-1). The expression of PDX-1 also has been detected in various human pancreatic ductal adenocarcinoma (PDA) cell lines. This has made it possible to generate a cancer cell-specific gene expression system to treat human pancreatic cancer. In this study, we have developed a cell-specific cytotoxic model of PDA cells using the expression of herpes simplex virus thymidine kinase (TK) under the control of the rat insulin promoter (RIP-TK). We have shown that the cell-specific cytotoxicity in human PDA cells depends on the presence of PDX-1. Our results also demonstrate that in vivo PDA-specific cytotoxicity can be achieved with RIP-TK using an intraperitoneal liposomal gene delivery method followed by a short period of ganciclovir treatment in severe combined immunodeficient (SCID) mice. Furthermore, PDX-1 protein was found in all six freshly isolated human pancreas cancer specimens and two liver metastasis samples that were group-tested, suggesting the feasibility of using RIP-TK gene therapy in humans. This study may provide an alternative strategy for the future treatment of pancreatic cancer.
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PMID:Cell-specific cytotoxicity of human pancreatic adenocarcinoma cells using rat insulin promoter thymidine kinase-directed gene therapy. 1545 66