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)

Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor beta (TGF-beta). Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-beta expression may enhance their immunogenicity and make them more suitable for active tumor immunotherapy. Subcutaneous immunizations of tumor-bearing animals with 9L cells genetically modified to inhibit TGF-beta expression with an antisense plasmid vector resulted in a significantly higher number of animals surviving for 12 weeks (11/11, 100%) compared to immunizations with control vector-modified 9L cells (2/15, 13%) or 9L cells transduced with an interleukin 2 retroviral vector (3/10, 30%) (P < 0.001 for both comparisons). Histologic evaluation of implantation sites 12 weeks after treatment revealed no evidence of residual tumor. In vitro tumor cytotoxicity assays with lymph node effector cells revealed a 3- to 4-fold increase in lytic activity for the animals immunized with TGF-beta antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells. These results indicate that inhibition of TGF-beta expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-beta antisense gene therapy for TGF-beta-expressing tumors.
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PMID:Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. 861 Jan 41

The authors report a case of radiation-associated intracerebral gliosarcoma with fibrosarcomatous predominance, arising at the site of a low-grade glioma treated 10 years previously. The features of this case conform to the accepted criteria for radiation-induced tumour, in that the tumour developed within the radiation field, differed dramatically in histologic features from the original tumour and did not develop until 10 years after treatment. Although such tumours are most uncommon, this case suggests that radiation-induced gliosarcoma should be considered in the differential diagnosis of recurrent mass at the site of a treated intracranial neoplasm.
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PMID:Radiation-associated gliosarcoma. 864 Apr 19

Earlier studies have shown that genetically engineered herpes simplex viruses (e.g., HSV-1) are effective in killing malignant tumor cells both in vitro and in various murine tumor models. This report focuses on a panel of five genetically engineered viral mutants of the gamma(1)34.5 gene, which was shown previously to cause reduction in viral replication and associated neurovirulence of HSV. These include R3616, which has both copies of gamma(1)34.5 deleted, R4009, which has a stop codon inserted after codon 28 in both copies of the gamma(1)34.5 gene, R849, which contains a lacZ gene inserted in place of the gamma(1)34.5, R908, which lacks 41 codons in frame after codon 72 of the gamma(1)34.5, and R939, which carries a stop codon precluding the translation of the COOH-terminal domain of the gamma(1)34.5 gene. We report the following: (a) all five mutant HSVs were avirulent in experimental animals but were cytotoxic for human tumor cells in vitro and in vivo; (b) the gamma(1)34.5- HSV replicated in human glioma cells almost as efficiently as wild-type HSV-1(F) based on replication assays, in situ hybridization for viral DNA, and expression of infected cell protein 27; (c) capacity of mutant HSVs to kill human cells derived from glioblastoma multiforme (CH-235MG, D-37MG, D-54MG, D-65MG, U-251MG, U-373MG, and SK-MG-1), anaplastic astrocytoma (Hs-683), anaplastic glioma (U-87MG and U-138MG), gliosarcoma (D-32GS), or normal human astrocytes demonstrated that glioma cells varied in their susceptibility to HSV-mediated cytotoxicity and that cultured astrocytes were two to three orders of magnitude less susceptible to killing than were malignant glia; and (d) scid mice, which received 0.5 or 5 x 10(6) plaque-forming units of R4009, either were coinoculated at the time of intracranial transplantation with 106 U251MG or D-54MG human glioma cells or received the cells intratumorally 5 days after tumor induction and experienced significant increases in median survivals, with no histopathological indication of an infectious encephalitic process. Genetically engineered gamma(1)34.5- HSV mutants appear to be a potentially safe biotherapeutic agent for experimental treatment of uniformly fatal malignant brain tumors.
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PMID:Evaluation of genetically engineered herpes simplex viruses as oncolytic agents for human malignant brain tumors. 910 52

Cyclopentenyl cytosine (CPEC) exerts an antiproliferative effect against a wide variety of human and murine tumor lines, including a panel of human gliosarcoma and astrocytoma lines. This effect is produced primarily by the 5'-triphosphate metabolite CPEC-TP, an inhibitor of cytidine-5'-triphosphate (CTP) synthase (EC 6.3.4.2). Because previous studies with human glioma cell lines utilized cells in long-term tissue culture, we have undertaken to determine whether the activity of CPEC in such model systems is also demonstrable in freshly excised human glioblastoma cells. Glioma cells obtained at surgery and in log phase growth were exposed to the drug at levels ranging from 0.01 to 1 microM for 24 h, and CPEC-TP and CTP levels were determined by HPLC. Dose-dependent accumulation of CPEC-TP was accompanied by a concomitant decrease in CTP pools, with 50% depletion of the latter being achieved at a CPEC level of ca. 0.1 microM. Human glioma cell proliferation was inhibited 50% by 24-h exposure to 0.07 microM CPEC. Postexposure decay of CPEC-TP was slow, with a half-time of 30 h. DNA cytometry showed a dose-dependent shift in cell cycle distribution, with an accumulation of cells in S-phase. The pharmacological effects of CPEC on freshly excised glioblastoma cells are quantitatively similar to those seen in a range of established tissue culture lines, including human glioma, colon carcinoma, and MOLT-4 lymphoblasts, supporting the recommendation that the drug may be advantageous for the treatment of human glioblastoma.
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PMID:Antiproliferative effects of cyclopentenyl cytosine (NSC 375575) in human glioblastoma cells. 922 Apr 96

Dexamethasone is used frequently in brain tumor therapy of patients. In animal models it is known to inhibit the angiogenesis of solid tumors. We addressed the question, if this is also true in brain tumors. C6 malignant glioma and 9L gliosarcoma cells were implanted into rat-brains. Dexamethasone 3 mg/kg/d intraperitoneal increased the survival compared to saline treated controls. The tumors size and the vascular density were smaller in the dexamethasone groups in both models. In vitro dexamethasone inhibited the growth of the C6 cells but not of 9L cells. Thus the growth inhibition of brain tumors in vivo appeared to be mediated partly by direct growth inhibition of tumor cells in C6 cells but additionally by antiangiogenesis in both tumor models. Several in vitro models were used to address the mechanisms of antiangiogenesis. There was no effect of dexamethasone on the proliferation of central nervous endothelial cells and no effect on the formation of capillary like structures on matrigel. Dexamethasone inhibited, however, the formation of capillary like structures in a coculture model with glioma cells in vitro. Surprisingly, progesterone had the same effect in this model. The in vitro effect was mediated via glucocorticoid receptors since receptor antagonists could inhibit it. The primary target appeared to be the tumor cell because only this cell had the complete set of receptors. These data show, that antiangiogenic therapeutic effects are possible by influencing primarily the tumor cell. This way of targeting might be of value for future developments of new strategies.
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PMID:Dexamethasone inhibits glioma-induced formation of capillary like structures in vitro and angiogenesis in vivo. 929 62

The antitumor activities of recombinant human tumor necrosis factor-alpha (rH-TNF alpha) and liposome-entrapped rH-TNF alpha were evaluated in various glioma cell lines and a rat brain T9 gliosarcoma model. rH-TNF alpha had a direct cytotoxic activity against various glioma cell lines in vitro, and indirect cytotoxic activity against gliosarcoma (T9) in vivo. Liposome-entrapped rH-TNF alpha had increased direct cytotoxic activity in vitro, and against experimentally induced brain tumors in vivo. The effects in vivo were probably due to vascular damage of the tumor vessels as shown by histological examination and activation of cytotoxic macrophages as shown in vitro. These results indicate that the general or local administration of liposome-entrapped rH-TNF alpha may become a useful adjunct treatment for malignant brain tumor.
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PMID:Antitumor activity of recombinant human tumor necrosis factor-alpha (rH-TNF alpha) and liposome-entrapped rH-TNF alpha. 936 33

Rat brain tumor models have been widely used in experimental neuro-oncology for almost three decades. The present review, which will be selective rather than comprehensive, will focus entirely on seven rat brain tumor models and their utility in evaluating the efficacy of various therapeutic modalities. Although no currently available animal brain tumor model exactly simulates human high grade brain tumors, the rat models that are currently available have provided a wealth of information on in vitro and in vivo biochemical and biological properties of brain tumors and their in vivo responses to various therapeutic modalities. Ideally, valid brain tumor models should be derived from glial cells, grow in vitro and in vivo with predictable and reproducible growth patterns that simulate human gliomas, be weakly or non-immunogenic, and their response to therapy, or lack thereof, should resemble human brain tumors. The following tumors will be discussed. The 9L gliosarcoma, which was chemically induced in an inbred Fischer rat, has been one of the most widely used of all rat brain tumor models and has provided much useful information relating to brain tumor biology and therapy. The T9 glioma, although generally unrecognized, was and probably still is the same as the 9L. Both of these tumors can be immunogenic under the appropriate circumstances, and this must be taken into consideration when using either of them for studies of therapeutic efficacy, especially if survival is used as an endpoint. The C6 glioma, which was chemically induced in an outbred Wistar rat, has been extensively used for a variety of studies, but is not syngeneic to any inbred strain. Its potential to evoke an alloimmune response is a serious limitation, if it is being used in survival studies. The F98 and RG2 (D74) gliomas were both chemically induced tumors that appear to be either weakly or non-immunogenic. These tumors have been refractory to a variety of therapeutic modalities and their invasive pattern of growth and uniform lethality following an innoculum of as few as 10 tumor cells make them particularly attractive models to test new therapeutic modalities. The Avian Sarcoma Virus induced tumors and a continuous cell line derived from one of them, designated RT-2, have been useful for studies in which de novo tumor induction is an important requirement. These tumors, however, are immunogenic and this may limit their usefulness for survival studies. Finally, a new chemically induced tumor recently has been described, the CNS-1, and it appears to have a number of properties that should make it useful in experimental neuro-oncology. It is essential to recognize, however, the limitations of each of the models that have been described, and depending upon the nature of the study to be conducted, it is important that the appropriate model be selected.
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PMID:Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. 952 31

The clotting factor XIIIa (FXIIIa) has been shown to be present both in tumor cells and in tumor-associated macrophages of different neoplasms such as Hodgkin's disease, giant cell tumor of bone, malignant fibrous histiocytoma, meningeal tumors, and hemangiopericytoma. The biological significance of these findings, however, are still unclear. This study investigates the immunohistochemical distribution of FXIIIa in 186 tumors of the central nervous system (CNS) in order to evaluate its possible diagnostic or prognostic significance in neuro-oncology. High-grade gliomas such as glioblastoma, gliosarcoma, astrocytoma (grade III WHO), and ependymoma (III) as well as meningiomas and meningeal hemangiopericytomas consistently contained factor XIIIa-positive cells, whereas low-grade glial tumors did not do so. One desmoplastic medulloblastoma and one anaplastic schwannoma also showed FXIIIa-positive cells. With the exception of hemangiopericytomas, however, the major source of FXIIIa expression in all these tumors consisted of a subpopulation of tumor-associated macrophages, the exact role of which still remains unclear. Because of its non-discriminatory staining in a wide variety of CNS tumors, the differential diagnostic contribution of FXIIIa in neuro-oncology seems to be limited.
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PMID:Factor XIIIa-immunoreactivity in tumors of the central nervous system. 956 29

One approach to improving the specificity of gene therapy involves using radiosensitive promoters to activate gene expression selectively in the radiation field. In this study, we evaluated the ability of irradiation to regulate the transcription of a recombinant replication-defective adenovirus vector, Ad.Egr-1/lacZ, containing the radiation-inducible Egr-1 promoter driving the beta-galactosidase reporter gene in glioma cells. Transcripts of the Egr-1 gene in human and rat glioma cells were induced following irradiation with as little as 2 Gy. This dose was 10-fold less than previously reported, and comparable to doses of irradiation used clinically in standard fractionated radiotherapy for brain tumors. When 9L rat gliosarcoma cells were infected with Ad.Egr-1/lacZ in vitro and exposed to 2 Gy of external beam irradiation, there was a threefold increase in beta-galactosidase expression. Irradiation of intracerebral 9L tumors infected with the Ad.Egr-1/lacZ virus, using either external beam radiotherapy (2 Gy) or the thymidine analog 5-iodo-2'-deoxyuridine radiolabeled with the Auger electron emitter iodine-125 ([125I]IdUrd), also resulted in increased beta-galactosidase activity of the tumor cells. These results indicate that the use of viral vectors containing radiation-inducible promoters represents a novel therapeutic approach that enables gene therapy to be spatially and temporally regulated by ionizing radiation. These findings also support a potential role for radiation-inducible promoters in the treatment of malignant brain tumors.
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PMID:Transgene expression in malignant glioma using a replication-defective adenoviral vector containing the Egr-1 promoter: activation by ionizing radiation or uptake of radioactive iododeoxyuridine. 968 9

Overexpression of interleukin 4 (IL-4) can impair the tumorigenicity of glioma cells, but direct evidence of its antitumor efficacy after in vivo gene transfer into malignant gliomas has not been provided. To test this, we first injected into the brain of Sprague Dawley rats a 1:1 mixture of C6 rat glioblastoma cells and psi2.L4SN20 or E86.L4SN50 retroviral producer cells (RPCs), secreting 20 and 50 ng of IL-4/5 x 10(5) cells/48 h, respectively. Twenty-seven and 56% of rats receiving injections with these low- or medium-level IL-4 RPCs, respectively, survived tumor injection, whereas control rats died in about 1 month. E86.L4SN50 RPCs coinjected with 9L gliosarcoma cells into syngeneic Fischer 344 rats yielded similar results. A novel IL-4 RPC clone expressing higher levels of IL-4, E86.L4SN200, coinjected with 9L cells increased to 75% the fraction of long-term survivors and induced tumor regression in 50% of rats when injected into established 9L gliosarcomas. Cured rats developed an immunological memory because they rejected a challenge of wild-type 9L cells into the contralateral hemisphere. Magnetic resonance imaging was used to monitor 9L and C6 gliomas and gave direct evidence for tumor rejection in treated rats. Immunohistology showed inflammatory infiltrates in IL-4-treated tumors in which CD8+ T lymphocytes were more abundant, although CD4+ T lymphocytes, B lymphocytes, and macrophages were also present. Overall, these findings suggest that IL-4 gene transfer is a new, promising approach for treating malignant gliomas.
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PMID:Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin 4 gene. 997 13


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