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)

A crucial question in the study of tumor neuro-immunology concerns the capacity of the central nervous system to initiate and execute an immune response. In a 100% fatal rat malignant glioma model, genetically modified tumors secreting INF-gamma intracerebrally generate an immune response resulting in a substantial increase in survival time, tumor rejection and specific systemic immunity. Tumors modified to secrete IL-2 alone do not change the biologic behavior of transfected gliomas. INF-gamma induces elevated expression of major-histocompatibility-complex-class-I and -class-II molecules in microglia throughout the brain and invokes enhanced tumor infiltration by CD4, CD8 and NK cells. These findings demonstrate successful immunization against a central-nervous-system tumor by direct priming in the brain with a live growth-competent tumor vaccine.
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PMID:Priming in the brain, an immunologically privileged organ, elicits anti-tumor immunity. 946 18

Cytokines such as interleukin-1 (IL-1) and IL-6 stimulate the hypothalamic-pituitary-adrenal (HPA) axis. In addition, these proteins affect pituitary cell proliferation in vitro. Thymosin fraction 5 (TF5) is a partially purified preparation of the bovine thymus that enhances immune system functioning. Because TF5 similarly stimulates the HPA axis, we examined the effects of this preparation on neuroendocrine tumor cell proliferation. Cells of the PRL-secreting rat anterior pituitary adenoma, MMQ (5-50 x 10(3) cells/well), were exposed to vehicle (RPMI-1640 containing 2.5% FCS, 7.5% horse serum, and antibiotics) or TF5 (100-500 microg/ml) for up to 96 h and the proliferation of MMQ cells monitored using the MTT assay (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide). TF5-mediated inhibition of cell proliferation was dependent on both TF5 concentration and the initial MMQ cell number. Minimal reductions in optical densities resulted from exposure to 100 microg/ml TF5, whereas the highest concentration of this preparation (i.e. 500 microg/ml) completely blocked MMQ cell division. The concentration-dependent effects of TF5 were particularly striking at initial plating densities of 25 and 50 x 10(3) MMQ cells/well; in contrast, all concentrations of TF5 completely inhibited MMQ cell growth at 5 and 10 x 10(3) cells/well. The antiproliferative actions of TF5 on MMQ cells were demonstrable within 24 h and remained for up to 96 h as determined by the MTT assay and actual cell counts. Because the highest densities of MMQ cells were partially refractive to the antiproliferative effects of TF5, we examined the effects of PRL (1-1000 nM) and MMQ cell conditioned medium (50%) on TF5 inhibition of MMQ adenoma proliferation. The TF5 concentration-dependent inhibition of MMQ cell growth was largely reversed by the 50% conditioned medium, whereas PRL slightly potentiated the antiproliferative actions of TF5. The proliferation of the rat C6 glioma cell line (10-30 x 10(3) cells/well) demonstrated greater sensitivity to TF5: concentrations as low as 10 microg/ml TF5 inhibited C6 cell proliferation (P < 0.01), and near-maximal inhibition was noted at 200 microg/ml TF5. Significant reductions in MMQ and C6 cell viabilities accompanied decreases in cell number and morphological analysis indicated these cells were dying by apoptosis. The peptides thymosin alpha1 (T alpha1), thymosin beta4 (T beta4), MB35, and MB40 had no effect on either MMQ or C6 cell proliferation, indicating that these TF5 components are not the principle active peptides. Therefore, TF5 was further separated into 60 fractions by preparative reverse phase HPLC. HPLC fractions 17, 25, 26, and 27 significantly suppressed MMQ cell proliferation (P < 0.01) to the same extent as TF5; other HPLC fractions had no effect. These data demonstrate a new biological property of TF5: the inhibition of cell proliferation and the induction of apoptosis in neuroendocrine tumor cells. The proliferation effects were time and concentration dependent and could be partially reversed by an activity present in the MMQ cell conditioned medium. Thus, TF5 and cytokines have opposite effects on adenoma cells because IL-2 and IL-6 stimulate GH3 cell proliferation. We propose that circulating thymic peptides may act to prevent pituitary adenoma and glioma tumor formation, an action opposed by autocrine growth factors secreted by these tumors.
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PMID:Thymosin fraction 5 inhibits the proliferation of the rat neuroendocrine MMQ pituitary adenoma and C6 glioma cell lines in vitro. 952 5

Interleukin-15 (IL-15) is a novel cytokine which shares activities and receptor components with IL-2. To investigate the biological roles of IL-15 in the human nervous system, we examined the expression of mRNAs for IL-15 and the IL-15 receptor three subunits (IL-15alpha, IL-2Rbeta and IL-2Rgamma) in human neural cell lines and tissues using reverse transcription-polymerase chain reaction and Southern blot analysis. The constitutive expression of high levels of IL-15 mRNA was observed in all the cell lines examined, including Y79 retinoblastoma, IMR-32 neuroblastoma, SK-N-SH neuroblastoma, U-373MG glioma, KG-1-C glioma, NTera2 teratocarcinoma and neurons derived from NTera2 cells following treatment with retinoic acid (RA). Among these cell lines, IL-15 protein was detectable at high levels in culture supernatants of SK-N-SH cells and NTera2-derived neurons. The expression of an alternatively-spliced transcript of the IL-15 gene was up-regulated in NTera2 cells during RA-induced neuronal differentiation, suggesting the existence of differentiation-dependent transcriptional regulation. The expression of IL-15 mRNA was also identified in the human cerebral and cerebellar tissues, peripheral nerve and skeletal muscle, while the mRNAs for the complete set of IL-15R components were detectable only in U-373MG cells, cerebral and cerebellar tissues at significant levels. These results indicate that the expression of IL-15 but not of IL-15R mRNA is universal in human neural cell lines and tissues and raise the possibility that IL-15 acts as a neuroimmune regulatory factor in the human central nervous system.
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PMID:Interleukin-15, a T-cell growth factor, is expressed in human neural cell lines and tissues. 956 62

Interleukin 12 (IL-12) exhibits anti-tumor activity in a variety of laboratory models. Although IL-12 itself activates strong anti-tumor activity, the combination of vaccine therapy with IL-2-transduced tumor cells and systemic rIL-12 has been shown to cure tumor-bearing mice more effectively than either rIL-12 or IL-2-transduced tumor vaccines alone. In the present study, regression of brain tumors established in naive mice was obtained by combined administration of an intratumoral injection of a single dose of IL-2-producing glioma cells (SR/IL-2 cells) and recombinant IL-12. Intraperitoneal rIL-12 administration substantially delayed the growth of s.c. inoculated gliomas, but not of gliomas located in the brain. Although vaccination with SR/IL-2 cells alone was not effective against s.c. inoculated gliomas, the combination therapy of vaccination with irradiated SR/IL-2 cells and systemic rIL-12 was more effective than rIL-12 alone. In our brain-tumor model, intratumoral administration of irradiated SR/IL-2 cells and of rIL-12 remarkably prolonged survival as compared with untreated mice. Efficacy was reduced when studies were performed in mice depleted of CD8+ cells or NK cells. Mice cured of their intracerebral tumors by combined administration of SR/IL-2 cells and rIL-12 demonstrated protective immunity upon rechallenge. In summary, the therapeutic potential for control of tumor growth by intratumoral administration of IL-2-producing glioma cells and rIL-12 may be useful in the development of treatment for patients with glioma.
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PMID:Anti-tumor activity of interleukin-2-producing tumor cells and recombinant interleukin 12 against mouse glioma cells located in the central nervous system. 993 85

We subcutaneously inoculated parental and glioma cells genetically engineered to express interleukin-2 (SR/IL-2) into syngeneic mice. The tumor growth of the transfectants was slower than that of the parental cells. We then stereotactically inoculated transfectants into the brains of mice. The survival of the mice injected with parental cells was shorter than that of the mice inoculated with transfectants. SR/IL-2 cells were inoculated subcutaneously into the flank of mice, after which rmIL-12 was administered intraperitoneally (i.p.). The resultant transient tumor growth was followed by regression. rmIL-12 or saline were then injected i.p. into mice that had been inoculated in the brain with SR/IL-2 cells. There was no significant difference in survival time between the treated and control groups.
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PMID:Antitumor activity of interleukin 12 against interleukin 2-transduced mouse glioma cells. 1007 20

Interleukin-12 (IL-12), originally called natural killer cell stimulatory factor or cytotoxic lymphocyte maturation factor, has potential for use as an immunomodulator in cancer therapy because it significantly retards the growth of some murine tumors. In this study, we analyzed the antitumor effects of lymphocytes stimulated in vitro with both recombinant IL-2 (rIL-2) and rIL-12. When IL-12 was added to mouse splenocytes (SPCs) or human peripheral blood monocytes (PBMCs) incubated with IL-2 for > 4 days, IL-2-induced cytotoxicity against glioma cells was augmented. In contrast, IL-12 inhibited IL-2-induced lymphokine-activated killer (LAK) cell activity when added concurrently to cultures. The concentration of IL-10 induced by IL-12 increased in the supernatant of human PBMCs costimulated with IL-2 and IL-12. Endogenous IL-10 augmented the cytotoxicity of SPCs stimulated with IL-2 or IL-12 or both. However, tumor-bearing mice treated with PBMCs stimulated with both IL-2 and IL-12 did not survive longer than those treated with PBMCs stimulated with IL-2 alone (LAK cells).
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PMID:Antitumor activity of killer cells stimulated with both interleukin-2 and interleukin-12 on mouse glioma cells. 1033 84

Previously, we reported that IL-6 transduction attenuates tumor formation of a rat T9 glioma clone (termed T9.F). This study focuses on the mechanisms of the antitumor response elicited by IL-6 and the generation of glioma immunity. Ten days post s.c. inoculation of T9. F- or IL-6-secreting T9.F cells (T9.F/IL6/hi), tumor nodules were removed and their leukocytic infiltrate was analyzed by FACS with Ab markers for T cells, B cells, granulocytes, and monocytes. T9. F/IL6/hi tumors showed a marked increase in granulocytes as compared with parental T9.F tumors, and histological examination revealed that the granulocytes were neutrophils. Animals made neutropenic failed to reject T9.F/IL6/hi tumors. FACS analysis of 17-day T9. F/IL6/hi regressing tumors and T9.F progressing tumors did not reveal any significant differences in the leukocytic infiltrates. Tumor-specific effector cells were detected in the spleens harvested from animals bearing 17-day, regressing, T9.F/IL6/hi tumors. In vitro, these effector cells lysed T9.F cells, proliferated in response to T9.F stimulator cells, and produced Th1 cytokines (IL-2 and IFN-gamma) but not the Th2 cytokine, IL-4, when cocultured with T9.F stimulator cells. Rats that had rejected s.c. T9.F/IL6/hi tumors displayed a delayed-type hypersensitivity response when injected with viable T9.F cells in the contralateral flank. Passive transfer of spleen cells from these animals transferred glioma immunity to naive recipients and depletion of CD3(+) T cells, before transfer, completely abolished immunity, whereas depletion of CD8(+) T cells had moderate inhibitory effects on the transfer of immunity.
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PMID:IL-6 secretion by a rat T9 glioma clone induces a neutrophil-dependent antitumor response with resultant cellular, antiglioma immunity. 1112 84

Recombinant viruses can produce cytokines in tumors mobilizing an immune response to tumor cells. In this study, the authors investigated gene expression, in vivo antitumor efficacy, and safety of attenuated recombinant vaccinia virus (rVV) carrying murine cytokine genes interleukin (IL)-2 (rVV-mIL-2), IL-12 (rVV-mIL-12), and both IL-2 and IL-12 (rVV-2-12) in an athymic nude mice model. Significant tumor inhibition (p < 0.05) was observed in a preestablished subcutaneously implanted C6 glioma model using rVVs at doses ranging from 10(2) to 10(7) plaque forming units (PFU). An antitumor effect did not depend on the dose of the rVV-mIL-2 and rVV-mIL-12 viruses. All constructed rVVs induced a high level of cytokine expression in vitro and in vivo. Most groups injected with high doses of recombinant viruses encoding cytokine genes (10(5) to 10(7) PFU) showed signs of cytokine toxicity, whereas in the low-dose treatment groups (10(2) to 10(3) PFU) toxicity was greatly reduced. The antitumor activity of rVV-mIL-12 was associated with increases in both the percentage and number of natural killer T cells in the spleen. Local detection of interferon-y and tumor necrosis factor-alpha was also correlated with tumor growth arrest induced by the treatment. High-dose VV control vector per se induced tumor inhibition by activating Mac-1+ cells in blood, but the antitumor effect was less pronounced compared with rVV-carrying cytokine genes (p < 0.05). These results suggest that attenuated recombinant strains of VV at low doses may potentially be efficient vectors for cancer immunotherapy.
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PMID:Low-dose vaccinia virus-mediated cytokine gene therapy of glioma. 1121 Nov 48

Immunotherapies, although promising in preclinical studies, have not yet enhanced the survival of patients with glioblastomas. To further understand the immunobiology of glioblastomas in clinical settings, we examined 53 cytokine or cytokine receptor transcripts in 12 human glioblastomas and 6 human glioblastoma cell lines and correlated the findings with the degree of inflammation. Multi-probe RNase protection assays were used to examine Th1, Th2, and Th3 cytokine and cytokine receptor expression. Th2 [interleukin (IL)-6, leukemia inhibitory factor and oncostatin M] and Th3 (transforming growth factor-beta1, 2, 3) cytokine and their receptor transcripts were strongly expressed in almost all glioblastomas and glioma cell lines. Two other Th2 cytokine receptor subunit transcripts (IL-4Ralpha and IL-13Ralpha) were also commonly detected. In contrast, although Th1 cytokine receptors tumor necrosis factor (TNF) RI, interferon (IFN)-gammaRalpha, IFN-gammaRbeta, were detected, their cytokines (IFN-gamma, TNF-alpha, lymphotoxin-alpha) were not. Transcripts for IL-2 family cytokine (IL-2, IL-7, IL-9, IL-15) and receptors (IL-2Ralpha, IL-2Rbeta, gammac, IL-7Ralpha, IL-9Ralpha, IL15Ralpha) and IL-12 family cytokine (IL-12p40) and receptors (IL-12Rbeta1 and IL-12beta2) were essentially absent in both tumors and cell lines. Immunohistochemical methods showed sparse T lymphocyte infiltrates and numerous microglia in the glioblastomas. This pattern indicates an 'immunosuppressive status' in glioblastomas and could account for the failure of immunotherapy in such tumors.
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PMID:Cytokine and cytokine receptor mRNA expression in human glioblastomas: evidence of Th1, Th2 and Th3 cytokine dysregulation. 1181 Jan 84

Cytotoxins directed to interleukin-4 receptors have shown to mediate relatively selective cytotoxicity against a variety of human cancer cells in vitro and in vivo. In an ongoing Phase I clinical trial, a recombinant protein comprised of circularly permuted IL-4 fused to a mutated form of Pseudomonas exotoxin (the fusion protein termed IL-4(38-37)-PE38KDEL or cpIL4-PE) has shown antitumour activity against malignant glioma. Human medulloblastomas are neuroectodermal tumours that occur in children and have a poor prognosis. The goal of this study was to determine whether human medulloblastoma derived cell lines express interleukin-4 receptor and whether interleukin-4 receptor expression is accompanied by sensitivity to cpIL4-PE. Medulloblastoma cell lines express interleukin-4 receptor at the protein and mRNA levels as determined by binding, indirect immunofluorescence and RT--PCR studies. These cells expressed IL-4Ralpha (also known as IL-4Rbeta) and IL-13Ralpha1 (also known as IL-13Ralpha') chains, however common gamma(c), a component of the interleukin-4 receptor system in immune cells was not detected. Consistent with the expression of IL-4R, cpIL4-PE was found to be highly and specifically cytotoxic to four of five medulloblastoma cell lines. Susceptibility of medulloblastoma cell lines to cpIL4-PE seemed to correlate closely to the functional IL-4 binding sites in general as demonstrated by 125I-IL-4 binding, but did not seem to correlate with mRNA or cell surface immunoreactive receptor protein expression. The sensitivity of medulloblastoma cells to cpIL4-PE could be eliminated by concurrent incubation with IL-4 or IL-13, but not with IL-2. None of these cell lines showed any change in proliferation upon treatment with exogenous IL-4. These studies establish the interleukin-4 receptor as a medulloblastoma-associated target for possible tumour-directed cancer therapy. Further studies are warranted to investigate interleukin-4 receptor expression in primary medulloblastoma tumours and sensitivity to cpIL-4PE in vitro and in vivo.
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PMID:IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein. 1187 May 21


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