Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that retrovirus-mediated genes were transferred to mouse glioma cells in a meningeal gliomatosis model (Yamada et al.: Japanese Journal of Cancer Research 83:1244-1247, 1992). This retrovirus vector contains the Escherichia coli. beta-galactosidase (beta-gal) gene as a marker for integration of the lacZ gene, which is controlled by the SV40 early promoter. We investigated whether lacZ genes could be specifically controlled in mouse glioma cells by glial-specific promoters, including the 2.5 kb 5' flanking region of the mouse glial fibrillary acidic protein (GFAP) gene, the 1.3 kb 5' flanking region of the myelin basic protein (MBP) gene, and the 1.5 kb 5' flanking region of the myelin proteolipid protein (PLP) gene. Psi-2 packaging cells were transfected with each retrovirus vector (GFAP promoter-, MBP promoter-, and PLP promoter-lacZ) and the infectious virus particles were recovered from the supernatants. Blue staining for beta-gal was detected in various fibroblast, myeloma, and glioma cell lines transduced with the retrovirus BAG vector. On the other hand, blue staining was only detected in glioma cells after transduction with the lacZ gene-bearing retrovirus controlled by glial-specific promoters. The strongest promoter activity was detected after transduction with the retrovirus in which the MBP promoter controlled the lacZ gene. Mouse glioma cells transduced with retrovirus containing the MBP promoter directing the herpes simplex virus type 1 thymidine kinase (HTK) gene were extremely sensitive to ganciclovir, while the parental cells and cells transduced with retrovirus containing the lacZ gene were not sensitive to ganciclovir.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective expression of foreign genes in glioma cells: use of the mouse myelin basic protein gene promoter to direct toxic gene expression. 750 43

The thymidine kinase (tk) gene of herpes simplex virus type 1 (HSV-1) was transduced into three glioma cell lines (T98, U251MG, T9) using a retrovirus vector. The supernatants of viral producer cell line PA317/LTRNL was used for infection and three transduced cell lines (T98/LTRNL, U251MG/LTRNL, T9/LTRNL) were established. The toxicities of the anti-herpetic drugs, acyclovir and gancyclovir, were evaluated in vitro. The cytotoxicities of acyclovir and gancyclovir to the HSV-1 tk gene-transduced cells increased 100-1000 fold compared to the non-transduced parental cell lines. The cytotoxic effect of gancyclovir was higher than that of acyclovir, requiring a concentration of less than 0.31 microM to obtain 50% inhibition. Deoxyribonucleic acid analysis of the gancyclovir-treated cells demonstrated fragmentation, suggesting that apoptosis is involved in the mechanism of cell death. The HSV-1 tk gene-transduced cells were co-cultured with parental cells and treated with gancyclovir. More than 95% of cells were killed in a mixture ratio of 1:1, suggesting that the "bystander effect" operated in this system. Selective transduction of HSV-1 tk gene into glioma cells using a retroviral vector and treatment with gancyclovir is a promising therapy for patients with malignant glioma.
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PMID:Retroviral transfer of herpes simplex thymidine kinase gene into glioma cells causes targeting of gancyclovir cytotoxic effect. 752 64

Retroviral vector is often used for gene therapy of malignant tumors. The main characteristic of this vector is that it integrates only into the genes of dividing and proliferating cells. Glioma cells proliferate actively, while surrounding normal brain cells rarely divide. Thus, we can expect the recombinant retrovirus modified to express cytotoxic genes to kill glioma cells selectively. However, this characteristic of specific toxicity to the dividing cells is also observed in many chemotherapeutic agents, and it is well known that they cause severe side effects, such as bone marrow suppression or diarrhea caused by simultaneous toxicity of the drugs to proliferating bone marrow cells or intestinal epithelial cells, respectively. We have cloned many genes which are specifically expressed in brain, and identified their promoter regions conferring tissue-specific expression. If we use the brain-specific promoters to regulate the expression of the toxic genes, these genes may not be expressed in the myeloid cells or intestinal epithelial cells, even if they were infected with the retrovirus. Therefore, we searched for brain-specific promoters which are also active in glioma cells to kill glioma cells specifically. Then, MBP promoter showed the strongest promoter activity in mouse glioma cells. These mouse glioma cells transduced with retrovirus containing the MBP promoter directing the herpes simplex virus type 1 thymidine kinase (HTK) gene were extremely sensitive to ganciclovir, even when transduced with the MBP promoter-HTK gene-containing retrovirus. And we could get complete remission in the mouse brain tumor models, which were transfected HTK genes in more than 25% glioma cells, with ganciclovir.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Selective gene therapy of malignant gliomas using brain-specific promoters: its efficacy and basic investigations]. 752 68

Cells expressing the herpes simplex-thymidine kinase (HS-TK) gene as a consequence of retroviral transduction, as well as TK-negative (TK-) bystander cells, can be killed by treatment with ganciclovir (GCV). In vitro, this "bystander effect," has been attributed to metabolic cooperation through gap junctions or to the uptake of apoptotic vesicles. We show that GCV treatment kills TK-negative U-87 glioma cells cocultured with cells that express TK (TK+) but that have lost the capacity for releasing retroviral particles. A photometric enzyme immunoassay identifies histone-associated DNA fragments, typical of apoptosis, in the cytosol of GCV-treated TK+ cells, and apoptotic features are also demonstrated by ultrastructural studies. Northern blot analysis and the reverse transcription polymerase chain reaction (PCR) show that connexin 43, a major constituent of gap junctions, is expressed in TK+ and U-87 cells. The size of U-87 tumors in nude mice subsequently injected with TK+ cells and GCV is not significantly different than in untreated animals; whereas, after injecting 1:1 mixtures of U-87 and TK+ cells, GCV treatment only causes a temporary regression of tumor growth. On the contrary, when the injected mixtures contain PA317.STK.SBA (a retroviral producer cell line that can transduce efficiently the HS-TK gene) and U-87 cells, tumors are destroyed effectively by GCV treatment. Thus, an experimental setting in which U-87 gliomas are matched with cells that are able to express, but not to transduce, the HS-TK gene indicates that the bystander effect kills U-87 cells in vitro by mechanisms associated with apoptotic death. In vivo, this effect is not sufficient to restrain the tumor growth taking place in immunodeficient animals.
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PMID:The "bystander effect": association of U-87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice. 754 76

1. The transcriptional regulation of the rat brain L-type calcium channel alpha 1D subunit (RB alpha 1D) gene was investigated using NG108-15 neuroblastoma-glioma cells. 2. Differentiation of NG108-15 cells in the presence of prostaglandin E1 or retinoic acid resulted in the appearance of mRNA encoding the RB alpha 1D subunit detected using Northern blot analysis. 3. A rat genomic DNA library was screened, and a 15.2-kb clone was isolated and partially sequenced which included part of the 5' upstream sequence through the initial part of intron 2 of the RB alpha 1D gene. 4. Deletion analysis, using a CAT reporter gene and transfected NG108-15 cells, revealed that the 1.2-kb 5'-upstream sequence from the RB alpha 1D gene contains cis-acting positive and negative regulatory elements. A deletion of the 3' end of exon 1 also suggested the presence of regulatory elements in the first exon. 5. DNase footprinting of exon 1 of the RB alpha 1D gene revealed two regions protected from digestion by specific protein binding, and the second region included an (ATG)7 trinucleotide repeat sequence. Electrophoretic mobility shift assays confirmed nuclear protein(s) binding to the (ATG)7 sequence. 6. The (ATG)7 sequence functions as a enhancer when linked to a thymidine kinase promoter and a CAT reporter gene. 7. These results provide the initial description of the transcriptional regulation of the RB alpha 1D gene and identify a novel enhancer that consists of an (ATG)7 trinucleotide repeat sequence.
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PMID:Transcriptional regulation of the neuronal L-type calcium channel alpha 1D subunit gene. 755 31

Using a rat C6 brain tumor model, we studied the antitumor effects of Herpes simplex virus type 1 thymidine kinase (HSV-tk) gene transfer followed by ganciclovir treatment. C6 glioma cells were transfected in vitro with the HSV-tk gene, and tested for their sensitivity to ganciclovir. Although there was no surviving cell at a 30 microM ganciclovir concentration, unmodified C6 cells were not affected by the drug. For in vivo experiments, intracerebral tumors were induced in rats by stereotactic injection of 10(4) HSV-tk-modified C6 cells. Ten days later, the animals were treated with intraperitoneal injections of ganciclovir for 21 days. The tumors evolution was evaluated by high resolution magnetic resonance imaging. In 33% of the rats, the signal intensity of the tumors became heterogeneous, with development of highly hyperintense areas, and a complete tumor regression was subsequently noted. Histological examination of successfully treated tumors revealed progressive necrosis with formation of cysts. The survival time of the HSV-tk/ganciclovir treated animals was consistently increased, all rats surviving more than 30 days and 33% of them being still alive after 80 days.
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PMID:Ganciclovir mediated regression of rat brain tumors expressing the herpes simplex virus thymidine kinase imaged by magnetic resonance. 759 56

The antiviral agents ganciclovir, 1-beta-D-arabinofuranosylthymine (araT), acyclovir, and 5-iodo-5'-amino-2',5'-dideoxyuridine were cytotoxic to rat C6 glioma cells expressing retrovirally transferred herpes simplex virus (HSV) type 1 thymidine kinase (TK) coding sequence, with concentrations that inhibited cell survival by 50% (IC50 values) of 0.06, 3, 13, and 23 mumol/L, respectively. In C6 cells not expressing HSV-TK, the IC50 value for ganciclovir was 140 mumol/L and a concentration of 1 mmol/L killed more than 99% of the cells. The other antiviral agents tested were less toxic in nontransduced cells. Compared with retrovirally transduced cells, transduction of C6BU1 cells with an adenovirus vector containing the coding sequence for HSV-TK (Ad.RSVtk) increased the cellular activity of the viral kinase up to 600-fold with increasing multiplicity of infection (MOl). Cells transduced with Ad.RSVtk exhibited as much as a fivefold and 12-fold decrease in IC50 value for ganciclovir and araT, respectively, compared with retrovirally transduced cells. Sensitivity to antiviral drugs increased with increasing exposure to Ad.RSVtk, with IC50 values of 0.6 and 0.005 mumol/L for araT and ganciclovir, respectively, at an MOl of 1000. These data suggest that adenoviral transfer of HSV-TK will allow the use of less toxic drugs or lower concentrations of toxic drugs such as ganciclovir for directed antitumor therapy in vivo.
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PMID:Enhanced cytotoxicity of antiviral drugs mediated by adenovirus directed transfer of the herpes simplex virus thymidine kinase gene in rat glioma cells. 762 Dec 41

A study developed to test the hypothesis of a possible relationship between metabolic modifications and chromosomal imbalances in solid tumors leads us to investigate the metabolism of purine nucleotides in human gliomas. In order to assess the representativeness of experimental models frequently used, the activities of nine enzymes involved in the synthesis and in the catabolism of purine nucleotides were measured on samples of normal brain, primary and xenografted glial tumors and cell cultures established from human gliomas. In parallel, two enzymes involved in pyrimidine metabolism were also studied on the same samples. The results highlight the low activity of the purine metabolism in human gliomas when compared to normal brain, tissue with low proliferative activity. On the contrary, the pyrimidine metabolism in human gliomas is increased by comparison to normal brain. For the purine metabolism, few differences are observed between enzyme activities calculated in primary glial tumors, xenografts and cells in culture. In grafted tumors and cell cultures, the activity of this metabolism is similar or lower than in normal brain, except for inosine monophosphate dehydrogenase. However, for the pyrimidine metabolism, significantly differences are observed between primary glial tumors, grafted glial tumors and cell cultures. The thymidine kinase/thymidylate synthetase ratio depends on the model studied. These results point out the problem of the representativeness of these models, especially when used for experimental therapeutic studies. This metabolic study also underlines that all results should be interpreted carefully and that the limits for the use of these two experimental models should always be clearly exposed.
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PMID:[Nucleotide metabolism in human glioma: comparative study of primary tumors, grafted tumors on nude mice and cell cultures]. 770 46

The efficacy of adenovirus (ADV)-mediated gene therapy to treat brain tumors was tested in a syngeneic glioma model. Tumor cells were transduced in situ with a replication-defective ADV carrying the herpes simplex virus thymidine kinase (HSV-tk) gene controlled by the Rous sarcoma virus promoter. Expression of the HSV-tk gene enables the transduced cell to convert the drug ganciclovir to a form that is cytotoxic to dividing cells. Tumors were generated in Fischer 344 rats by stereotaxic implantation of 9L gliosarcoma cells into the caudate nucleus. Eight days later, the tumors were injected either with the ADV carrying the HSV-tk (ADV-tk) gene or a control ADV vector containing the beta-galactosidase (ADV-beta gal) gene and the rats were treated with either ganciclovir or saline. Tumor size was measured 20 days after implantation of 9L cells or at death. Rats treated with ADV-beta gal and ganciclovir or with ADV-tk and saline had large tumors. No tumors were detected in animals treated with ADV-tk and with ganciclovir at doses > or = 80 mg/kg. An infiltrate of macrophages and lymphocytes at the injection site in animals treated with ADV-tk and ganciclovir indicated an active local immune reaction. In survival studies, all animals treated with ADV-tk and ganciclovir have remained alive longer than 80 and up to 120 days after tumor induction whereas all untreated animals died by 22 days. These results demonstrate that ADV-mediated transfer of HSV-tk to glioma cells in vivo confers sensitivity to ganciclovir, and represents a potential method of treatment of brain tumors.
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PMID:Adenovirus-mediated gene therapy of experimental gliomas. 788 26

We have found that thymidine kinase expression is a major radioresponse determinant in rat glioma cells. Cells that lack thymidine kinase expression are significantly more radiosensitive relative to the wild-type cells. The degree of sensitization is large, particularly at the dose levels used in fractionated radiotherapy. The difference in low dose survival can be accounted for by a marked difference in the ability of the cells to undergo repair of sublethal damage. When herpes thymidine kinase was introduced into the thymidine kinase-deficient mutant cells, radioresistance was partially restored, and sublethal damage repair was also enhanced. All other radiobiological responses, including DNA double-strand break repair, potentially lethal damage repair, G2 arrest, and cell cycle distribution, appeared similar among the cell lines. These data suggest that the thymidine kinase enzyme or its cellular gene may be an excellent therapeutic target to increase radiosensitivity and thereby, to enhance the radiocurability of malignant brain gliomas.
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PMID:Expression of thymidine kinase is essential to low dose radiation resistance of rat glioma cells. 792 6


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