Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Total regression of malignant brain tumors was observed in Wistar rats after retrovirus-mediated gene therapy. Tumors were induced by inoculation of C6 rat glioblastoma cells to a specific location in the rat brain and the tumors that developed were visualized by magnetic resonance imaging (MR). Retroviral vectors were constructed from a defective murine retrovirus to which the thymidine kinase (tk 1) gene from herpes simplex was added (HSV1tk). The vectors produced therapeutic viruses upon their introduction into retrovirus packaging cells. Delivery of the producer cells to the tumor mass and subsequent antiherpetic treatment eradicated the tumors completely, as observed using MRI. Some of the treated animals have been followed for over 8 months and show no signs of recurrence.
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PMID:Long-term rat survival after malignant brain tumor regression by retroviral gene therapy. 771 34

The platelet-derived growth factor (PDGF) A-chain gene is expressed in a tissue- and developmental stage-specific manner. Here we identify an S1 nuclease sensitive region within the first intron that functions as a negative regulatory element in HeLa but not in human glioblastoma (A172) cells in transient transfection assays. A 147 bp DNA fragment that contains this element functions in a position and orientation independent manner to negatively regulate both the PDGF A-chain promoter and the heterologous herpes simplex virus thymidine kinase (TK) promoter. The cell-type specific effect of this 147 bp DNA fragment is seen when it is located downstream but not upstream of the reporter gene driven by either the PDGF A-chain or TK promoters. The negative regulatory element has been localized to a 24 bp DNA sequence within the S1 sensitive site that retains negative regulatory activity and recognizes a nuclear protein in HeLa but not in A172 cells. Furthermore, the 24 bp element functions as a cell type-specific negative element independent of its position. These results suggest that a functional silencer within the first intron exhibits a non-B-form DNA structure under superhelical stress in vitro and may contribute to the cell type-specific transcriptional regulation of PDGF A-chain gene in vivo.
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PMID:An S1 nuclease-sensitive region in the first intron of human platelet-derived growth factor A-chain gene contains a negatively acting cell type-specific regulatory element. 812 85

The expression of connexin43, the primary gap-junction constituent of glial cells, was evaluated at the messenger RNA and protein levels in different grades of astrocytoma to investigate the relevance of gap junctions in herpes simplex virus-thymidine kinase (HSV-tk)-mediated gene therapy of brain tumors. Transduction of the retroviral-mediated HSV-tk gene into tumor cells with subsequent administration of ganciclovir has recently been used as an experimental therapeutic strategy for treatment of brain tumors. One aspect of this approach is the bystander effect, which augments the efficacy of this therapeutic approach. Glioblastoma cells with minimum levels of connexin43 protein were transfected with a connexin43 complementary DNA. These cells manifested a marked increase in the in vitro bystander effect, supporting the contention that the in vitro bystander effect is a consequence of metabolic cooperation between cells mediated by gap junctions. To assess relative levels of gap-junction protein expression in the relevant tumor type, we examined primary astrocytomas, primary astrocytoma cell cultures, and glioblastoma cell lines. Although most astrocytoma tumor samples expressed connexin43, they differed in the level of expression, with the greatest variation exhibited in high-grade astrocytomas. Primary glioblastoma cell cultures and established glioblastoma cell lines also displayed some variability in connexin43 levels. In aggregate, our results anticipate that glioblastomas will have a varied bystander effect during HSV-tk gene therapy depending on the level of connexin43 expression.
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PMID:Protein and messenger RNA expression of connexin43 in astrocytomas: implications in brain tumor gene therapy. 862 59

Herein we describe experiments showing that the early growth response gene 1 (EGR-1) promoter is sufficient to confer selective expression of the luciferase gene (Luc) in glioma cell lines exposed to ionizing radiation. Activity of the EGR-1 promoter was investigated in human glioblastoma cells using the plasmid vector, pEGR-Luc. The EGR-1 promoter gene directed radiosensitive expression of luciferase. This promoter showed high levels of activity (10-fold) in irradiated glioma cell lines as compared to basal levels of activity in nonirradiated cell lines. Maximum activation was detectable at 1-3 hr after stimulation with 20 Gy. The results also demonstrate that cells modified to contain the herpes simplex virus-thymidine kinase (HSV-tk) gene under control of the EGR-1 promoter become sensitive to treatment with the antiviral agent ganciclovir (GCV), whereas nonirradiated cells and nontransfected cells were unaffected by this agent. This results suggest that therapeutic genes can be expressed selectively in irradiated glioma cells. The results also indicate that the EGR-1 promoter can be used to induce exogenous genes selectively in radiation fields used for the treatment of malignant brain tumors.
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PMID:Activation of the radiosensitive EGR-1 promoter induces expression of the herpes simplex virus thymidine kinase gene and sensitivity of human glioma cells to ganciclovir. 866 75

The construction of a new retroviral vector, pSKV, is described. This vector carries two unique cloning sites, located between two Moloney leukemia virus-derived LTR, into which genes of interest may be introduced. The gene encoding hygromycin resistance (HyR) was subsequently introduced into one of the two sites, producing a second vector (pSKV/HyR) containing a unique SfiI site for the introduction of cDNA clones under the control of the cytomegalovirus (CMV) promoter (P-CMV). The cDNA (mH13), encoding a protein that has been shown to serve as a murine ecotropic retroviral receptor in transient assays, was cloned into the SfiI site (pSKV/HyR/mH13). Both constructs can be packaged into retroviral particles following transfection into an appropriate packaging cell line. Stable transfectants of the human glioblastoma cell line (U118MG) carrying each of these two constructs were generated by transfection and subsequent Hy selection. Clones expressing both the selectable marker and the mH13 gene, but not those expressing only the selectable marker, are shown to be susceptible to infection with murine ecotropic retroviral particles. These cells (HyR and mH13 positive) were then exposed to CRE/Xtk culture supernatant, a packaging cell line producing ecotropic retroviral particles carrying the HSV-TK (Herpes simplex virus-thymidine kinase) and neoR (neomycin-resistance) genes. Selection was in the presence of G418. In vitro growth of the U118MG/HyR/mH13/TK cells, but not that of the U118MG/HyR/mH13 cells, was inhibited by ganciclovir (GCV), indicating the successful transfer of HSV-TK by infection of human cells with murine retroviruses via the mH13 product.
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PMID:Infection of human cells by murine ecotropic viruses: retroviral vectors carrying the hygromycin resistance-encoding gene. 866 55

Four different transcripts encoding fibroblast growth factor 1 (FGF-1, also known as aFGF) have been previously identified in our laboratory. Among them, FGF-1.B is the major transcript expressed specifically in the neuronal cells in brain tissue. Using the transient transfection experiment in a glioblastoma cell line, U1240MG, that expresses 1.B, we previously identified two regulatory regions (RR1 and RR2) in the brain-specific promoter, FGF-1.B. In the present study, we showed that the minimal region required for the DNA-protein interaction in RR2 resides in an 18-base pair (-484 to -467) sequence, by using DNase I footprinting and methylation interference studies and electrophoretic mobility shift assays. This minimal cis-acting element was found to be sufficient in enhancing the reporter activity driven by the heterologous herpes simplex virus thymidine kinase promoter in the 1.B-positive U1240MG cell line. This enhancing effect, however, was not detected in a glioblastoma cell line, U1242MG, which is negative for 1.B expression. By electrophoretic mobility shift assays, we also identified a specific DNA-protein complex, namely complex I, which is specific for 1.B-positive cell lines and human brain tissue. By in situ UV cross-linking experiment, we further showed that complex I contains two major DNA-binding proteins of apparent molecular masses of 37 and 98 kDa. Our results suggest that the formation of complex I, resulting from the heterodimerization of a 37-kDa protein (1.B-specific) and a 98-kDa protein (ubiquitous) may likely be a prerequisite for the enhanced expression of 1.B transcript in neuronal cells.
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PMID:Transcriptional activation of fibroblast growth factor 1.B promoter is mediated through an 18-base pair cis-acting element. 905 60

The authors have used the thymidine kinase/ganciclovir system to block glioblastoma multiforme neoplastic cells in vivo, both in experimental animals and in two patients in which the more conventional therapies had been unsuccessful. In the Wistar rat it was found that the curability potential of the system is correlated with tumoral volume. Tumours smaller than 20 mm3 can be cured with defective retrovirus that do not carry the Herpes simplex thymidine kinase (Hsvtk) gene. While tumours smaller than 150 mm3 can regress totally by the kinase/ganciclovir system, those above that size cannot be cured by this treatment. In humans the situation seems very similar in that the authors have been unable either to reduce the tumour size of recurrent patients with tumour volumes larger than 100 cm2 applying the standard thymidine kinase/ganciclovir gene therapy or to prolong their survival time more than 8 months [7]. When a combination of size reduction by neurosurgery and gene therapy was used the survival time increased considerably. Two patients have been treated by partial surgery and repeated treatment with thymidine kinase/ganciclovir through an Ommaya reservoir connected to a catheter leading into the tumour cavity. The magnetic resonance imaging (MRI) of these patients show only a residual tumoral growth along side the tumoral bed. The procedure may be partially controlling the proliferation of cancerous cells, because, these two patients having recurrent glioblastoma, are alive 11 and 17 months after the beginning of the treatment.
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PMID:Gene therapy in brain tumours: implications of the size of glioblastoma on its curability. 923 25

The gene therapy strategy using the hsvl-thymidine kinase gene (TK) and ganciclovir (GCV) injections that has been used for treating human glioblastomas has not been as effective as expected after the first animal experiments. A better understanding of the different steps involved in this treatment, like gene transfer, gene expression, and sensitivity of the recipient cells, is needed. After proposing sensitivity criteria for the TK/GCV system and for the bystander effect, based on the levels of GCV that can be reached in vivo, we studied seven human glioblastoma cell lines (U87, U118, U251, SNB19, SNB75, SF295, SF539) for their sensitivity to the TK/GCV system. We also studied their in vitro bystander effect and their in vitro transfectability using LipofectAMINE as a transfection enhancer. Among six human glioblastoma cell lines stably transfected with the TK gene, five were sensitive to TK/GCV, and two had a good in vitro bystander effect. The in vitro transfectability of the cell lines tested was low (< or = 1%) compared to that of an established animal cell line, C6 rat glioma, in which 20-30% of the cells can be transfected routinely. According to this in vitro analysis, most of the glioblastoma cell lines should be sensitive to the TK/GCV system, but there is an urgent need for agents to increase transfection efficiency.
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PMID:Variable efficiency of the thymidine kinase/ganciclovir system in human glioblastoma cell lines: implications for gene therapy. 938 60

A promising strategy in the treatment of malignant gliomas involves the creation of Herpes Simplex Virus-thymidine kinase (HSV-tk) modified tumor cells. Some authors have observed complete tumor regression after ganciclovir (GCV) treatment of established gliomas transduced in vivo by the HSV-tk gene. Yet, further investigations did not confirm completely these results, even if confirmed the therapeutic potential of such a therapy. Using the rat C6 glioblastoma as a model of malignant brain tumor, we investigated the efficacy of in vivo and in vitro transduction of growing brain tumors with the HSV-tk gene, followed by GCV administration. The stereotactic injection into the left striatum of C6 cells mixed with retroviral producer cells and GCV treatment did not improve significantly the animal survival compared to controls. On the contrary, there was a significant prolongation of the survival of rats inoculated with C6 cells engineered in vitro to express the HSV-tk gene. Nevertheless, complete eradication of the tumors was not achieved. We also injected a group of six rats with a mixture of cells expressing the murine Interleukin-4 (IL-4) gene and C6 cells. IL-4 has been shown to produce the regression of experimental brain tumors. Our preliminary experience seems to confirm that hypothesis. Our results indicate that the outcome of HSV-tk gene therapy can be limited not only by low gene transfer but also by insufficient delivery of GCV to tumor cells. Combined strategies, based on contemporary transduction of HSV-tk and IL-4, may enhance the therapeutic perspectives of such a therapy.
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PMID:Perspectives for the gene therapy of malignant gliomas by suicide gene transfer. 944 75

Tumor cells transduced with retrovirus carrying the herpes simplex-1 virus thymidine kinase (HSV-tk) are capable of transforming the antiviral drug ganciclovir (GVC) into a metabolic form only toxic to dividing cells. The efficiency of this suicide gene therapy is increased by a "bystander" effect resulting not only in the death of the recipient cell, but also in the death of non modified surrounding cells. Even though the mechanism of this "bystander" effect remains to be elucidated, strong evidence suggest that the immune system plays a main role to achieve complete tumor eradication. In the present study we evaluate the efficiency of this suicide system on three different tumor models: one human melanoma, one murine melanoma, and a rat glioblastoma. Tumors were established by injection of tumor cells s.c. in nude and C57Bl/6 mice, respectively, and stereotactically into the brain of Sprague Dawley rats. Animals in the treated group were co-injected with packaging cells producing recombinant retrovirus carrying the HSV-tk gene, and followed by i.p. administration of GVC. In short term studies, we observed inhibition of tumor growth for all the tumor models evaluated (p < 0.01). In long term studies, using the C6 rat glioma line, 50% of the animals survived longer than 75 days (p < 0.0001), and were able to reject a contralateral challenges with C6 parental cells. Histological and immunohistochemical analysis showed the presence at an inflammatory infiltrate composed by T lymphocytes, macrophages and polymorphonuclear cells. These data demonstrate that suicide genes might represent an attractive form of cancer gene therapy in the treatment of brain tumors and their intracerebral dissemination.
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PMID:[Antitumor gene therapy using suicide genes]. 970 53


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