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)

Cytotoxic T lymphocytes specific for tumor-associated antigens are produced by exposing animals to tumor cells and stimulating lymphocytes from animals immunized in vitro with tumor cells and small amounts of interleukin-2 (IL-2). This study was designed to determine whether a fast-growing immunogenic avian sarcoma virus-induced glioma produces primed cytotoxic T lymphocyte precursors during its progression. Lymphocytes from intracerebral glioma-bearing rats generally failed to proliferate in vitro in response to immunization with tumor cells and IL-2 and, when proliferative responses were observed, the lymphocytes were not cytotoxic for glioma cells. However, when the same tumor was growing subcutaneously, lymphocytes proliferated and exhibited glioma-specific cytotoxicity when stimulated in vitro with autologous tumor cells and IL-2. Subcutaneous immunization of intracerebral glioma-bearing rats with tumor cells and adjuvant induced strong cytotoxic T lymphocyte responses. The results demonstrated that, while intracerebral tumor progression itself does not induce an anti-glioma immune response, immune responses to tumor-associated antigens may be induced by systemic immunization of tumor-bearing animals. The results suggest that the immunogenicity of brain tumors is masked by the immunologically privileged status of the brain, not by the induction of generalized immune suppression during tumor progression.
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PMID:Generation of cytotoxic immune responses during the progression of a rat glioma. 802 26

Lymphokine-activated killer (LAK) cells generated from peripheral blood lymphocytes incubated with recombinant interleukin-2 were transfected with the human tumor necrosis factor (TNF)-alpha gene by means of novel liposomes with a positive change on their surface. The cells secreted significant amounts of TNF-alpha into the culture medium and exhibited reinforcement of cytotoxicity toward a human glioma cell line (U251-SP), being three times more cytotoxic than nontransfected LAK cells. The mechanism for the reinforcement of cytotoxicity is considered to involve not only an increase in TNF-alpha secretion from LAK cells but also its expression on their surface. Intratumoral or intrathecal injection of LAK cells transfected with the TNF-alpha gene may be useful for the treatment of patients with malignant gliomas.
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PMID:Reinforced cytotoxicity of lymphokine-activated killer cells toward glioma cells by transfection with the tumor necrosis factor-alpha gene. 842 Dec 7

This in vitro study was aimed at restitution of transforming growth factor (TGF)-beta 2-mediated suppression of T-lymphocyte activation within malignant gliomas. In early-passage tumor cell cultures of two glioblastomas (HTZ-153 and HTZ-209) and one malignant astrocytoma classified as World Health Organization Grade III (HTZ-243), autologous peripheral blood mononuclear cells were activated by interleukin-1 alpha and interleukin-2 in vitro (lymphokine-activated killer cells) and tested for cytotoxic and proliferative activity. In expression studies (Western blot and Northern hybridization) of all three tumors, TGF-beta could be detected at the protein and messenger ribonucleic acid (mRNA) levels. A polyclonal anti-TGF-beta neutralizing antibody did not enhance lymphocyte proliferation upon stimulation with tumor targets (3H-thymidine incorporation) and slightly stimulated lymphocyte cytotoxicity against autologous target cells. Preincubation of target cells for 12 hours with TGF-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides (S-ODN's) did, however, enhance lymphocyte proliferation up to 2.5-fold and autologous tumor cytotoxicity up to 60%, compared to controls not treated with S-ODN's. Incubation of tumor cells with TGF-beta 2-specific S-ODN's resulted in decreased TGF-beta-specific immunoreactivity in cultured glioma cells, in reduced TGF-beta 2 protein concentration (Western blot), and in a change in the expression pattern of TGF-beta 2 mRNA's. These observations may have implications for in vivo and in vitro activation of a cellular immune response against autologous malignant glioma cells.
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PMID:The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. 848 77

The study demonstrated that RT2, a highly malignant anaplastic glioma, expresses antigens that make it susceptible to in vivo adoptive immunotherapy with cytotoxic T lymphocyte-containing immune cell populations. Rats were immunized with irradiated RT2 tumor cells and the adjuvant C. parvum. Lymphocytes from immunized rats were restimulated in vitro with irradiated RT2 tumor cells plus interleukin-2 (IL-2). The cells that proliferated and differentiated in vitro effectively killed RT2, but only low levels of cytotoxicity were observed against other histopathologically related and unrelated, syngeneic and allogeneic target cells. Adoptive transfer of immune cells combined with a 5-day course of systemic IL-2 produced specific regression of brain tumors growing as lung microfoci.
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PMID:Generation of cellular immune responses against a glioma-associated antigen(s). 849 37

Ten patients with recurrent malignant primary brain neoplasms were treated with adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2). Nine patients had supratentorial glioma and they received multiple intratumoral instillations of LAK cells through reservoir-catheter system or burrhole. The other patients with disseminated subarachnoid metastases from posterior fossa medulloblastoma received immunotherapy via lumbar subarachnoid route. A partial and transient clinical response was observed in two patients. following the therapy, and a cystic transformation of the essentially solid tumour was noted on the CT scans of these two patients. No significant clinical or radiological response to the treatment was observed in the remaining 8 patients. The results of this preliminary study reveal limitations of the regional intratumoral adoptive immunotherapy using currently available techniques and provide sufficient evidence of its effectiveness to warrant further investigations.
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PMID:Adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 for recurrent malignant primary brain tumors. 869 35

The efficacy of intrathecal treatment of leptomeningeal metastasis (LM) with interleukin-2 (IL-2) was evaluated in an animal model using Wistar rats inoculated intracisternally with 10(7) C6 glioma cells. Prior to the in vivo experiments the antiproliferative effects of human IL-2, and of murine IFN-gamma and TNF-alpha which are cytokines induced by IL-2 were tested in a colony forming assay. Only IFN-gamma caused a dose-dependent inhibition of colony formation. Twelve animals were treated intracisternally with either 10(5) IU IL-2 or control medium on day 0, 2, and 5 after tumor cell inoculation. Both IL-2 treated and sham-treated animals developed LM with a symptom-free survival of 7 to 9 days. There was no significant difference between treated and untreated animals regarding time to onset of symptoms and pattern of tumor growth. Infiltration of the tumor tissue with ED-1+ monocytes and macrophages, and CD8+ lymphocytes, however, was slightly increased in IL-2 treated animals. In a second experiment 4 non tumor-bearing Wistar rats were intracisternally injected with a single dose of 10(5) IU IL-2. These animals also showed slightly enhanced leptomeningeal infiltration with CD8+ lymphocytes compared to controls. We conclude that intrathecal application of high-dose IL-2 although eliciting a slight immune reaction within the leptomeninges does not inhibit leptomeningeal tumor growth or prolong symptom-free survival in our animal model of LM. These results raise doubt about the clinical efficacy of intrathecal IL-2 treatment in patients with LM.
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PMID:Intrathecal treatment of C6 glioma leptomeningeal metastasis in Wistar rats with interleukin-2. 884 52

Malignant brain neoplasms present great therapeutic challenges due to their extremely aggressive behavior and relative isolation by the blood-brain and blood-tumor barriers. Endothelial cells may be versatile platforms for delivering genes to solid tumors by virtue of their location at blood-tissue interfaces and their proliferation in response to endothelial mitogens produced by tumors. Immortalized rat brain endothelial cells that express the E. coli lacZ reporter gene and the gene for murine interleukin-2 (RBEZ-IL2) were co-inoculated with 9L glioma cells to Fisher rats to examine the effects of endothelial cell-based cytokine delivery on glioma growth in vivo. 9L glioma growth was not affected by the implantation of control RBEZ cells. The growth of subcutaneous and intracranial 9L gliomas was significantly inhibited by RBEZ-IL2 cells (P < 0.005 and P < 0.01, respectively) when compared to control transfected RBEZ cells. Rats receiving intracranial 9L glioma cells with RBEZ-IL2 cells showed increased survival (P < 0.001). Histologic and immunohistologic analysis showed enhanced activation of microglia/macrophages and CD8-positive T lymphocytes and/or natural killer cells within brain at sites of 9L inoculation with RBEZ-IL2 cells. This report establishes that immortalized endothelial cells can be used for cytokine gene delivery and to activate anti-tumor host responses to experimental gliomas within the central nervous system.
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PMID:Endothelial cell-based cytokine gene delivery inhibits 9L glioma growth in vivo. 888 66

The efficacy of gene therapy for glioma was examined using adeno-associated virus (AAV)-based vectors to deliver genes to experimental tumors in mice. Stereotactic injection of 2 x 10(5) U-251SP human glioma cells into the brains of nude mice produced tumors of 19.06 +/- 1.79 mm2 17 days after injection. Employing a high titer preparation of AAV vector containing the gene for beta-galactosidase (AAV-lacZ), dose-dependent transduction of U-251SP cells was seen in vitro. When 1.6 x 10(10) AAV-lacZ particles were directly injected into tumors in vivo, 30-40% of the cells along the needle track expressed beta-galactosidase. Transduction of U-251SP cells in vitro with an AAV vector containing a bicistronic gene encoding both herpes simplex thymidine kinase and human interleukin-2 (AAV-tk-IRES-IL2) rendered them sensitive to the cytocidal effects of ganciclovir (GCV) and IL-2 was produced in a dose-dependent manner. Cocultures of AAV-tk-IRES-IL2 transduced cells and nontransduced cells proved highly sensitive to GCV indicating the contribution of the bystander effect. Stereotactic delivery of 6 x 10(10) AAV-tk-IRES-IL2 particles into day 7 tumors in nude mice followed by administration of GCV for 6 days, resulted in a 35-fold reduction in the mean volume of tumors compared with controls. Normal brains did not suffer from any toxic effect of the administration of AAV-tk-IRES-IL2 and GCV. These results indicate that high titer AAV vector treatment may be safe and effective for in vivo gene therapy of human brain tumors.
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PMID:Gene therapy against an experimental glioma using adeno-associated virus vectors. 894 Jun 35

The neuroblastoma x glioma hybrid cell line NH15-CA2 was used to test the effects of two interleukins on neuronal Na+ channels. The cells were cultured in the presence of dibutyryl cAMP and retinoic acid, which yielded a high expression of Na+ channels so that the cells were excitable. Na+ currents were triggered and recorded in the whole-cell recording mode. Comparison of the effects of tetrodotoxin and mu-conotoxin established that the expressed Na+ channels were of the neuronal type. Bath-applied recombinant human interleukin-2 (rIL-2) had a reversible inhibitory effect on the Na+ currents, although to a lesser extent than on muscular Na+ currents (more than 1000 U/ml required for 50% block in NH15-CA2 cells vs 500 U/ml in myoballs). The current/voltage relationship was not affected by the presence of rIL-2, but the steady-state inactivation curve was shifted by -7.7 +/- 4.8 mV (mean +/- SD, n=18). Recombinant human interleukin-1beta (rIL-1beta), applied at 1000 U/ml, showed an inhibitory effect on the Na+ currents in about one-third of the cells tested. The mechanism of inhibition was different from that of rIL-2, as rIL-1beta seemed to cause a block without affecting voltage dependence or kinetics of the channels.
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PMID:Excitatory sodium currents of NH15-CA2 neuroblastoma x glioma hybrid cells are differently affected by interleukin-2 and interleukin-1beta. 901 18

It has been shown that adoptive immunotherapy can be curative for established malignant tumors. The key to this treatment lies in obtaining sufficient numbers of lymphocytes which are sensitized to recognize tumor antigens and carry out immunological reactions to destroy tumor cells. Reported here are the results of experiments to: 1) sensitize lymphocytes to the antigens of rat glioma cells and expand them ex vivo for use in adoptive immunotherapy, 2) characterize the cells of the expanded population, and 3) evaluate antitumor activity in a cohort of rats with well-established intracranial gliomas. Viable RT-2 glioma cells were injected into the hind foot pads of syngeneic Fischer 344 rats. After 10 days, the tumor draining lymph nodes (DLN) were harvested from the injected limbs and mechanically dissociated. The cells of the DLN were then suspended in culture medium supplemented with low dose interleukin-2 (IL-2) and incubated for 18 hours with Bryostatin-1 and ionomycin (Bryo/Io) to stimulate expansion. The cells were next washed to remove the Bryo/Io and resuspended in culture medium and IL-2. Population expansions of 40- to 100-fold were seen after 8 days. Flow cytometric analysis showed these cells to be a nearly pure population of T lymphocytes of the CD3+CD8+ phenotype. Intravenous injection of the ex vivo expanded DLN cells did not significantly improve survival of rats with a seven-day intracerebral RT-2 glioma, although, compared to untreated controls, the tumors of the treated animals were smaller, showed no necrosis, and appeared to be less infiltrative. Furthermore, the treated animals had a pronounced lymphocytic infiltration of their tumors with greater associated degrees of hemorrhagic change and peritumoral edema. When the ex vivo expanded DLN cells were intravenously injected into three-day intracerebral RT-2 glioma models, tumors were almost always eliminated and the animals survived their tumor challenge. We conclude that successful expansion of glioma-sensitized DLN lymphocytes is possible and that adoptive immunotherapy using these cells is capable of effectively limiting the progression of large gliomas, while totally eradicating small ones.
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PMID:Ex vivo expansion of tumor-draining lymph node cells using compounds which activate intracellular signal transduction. I. Characterization and in vivo anti-tumor activity of glioma-sensitized lymphocytes. 904 59


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