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)

The aim of this study was to evaluate whether interferon [IFN] can affect intracerebrally grown glioma and how alteration of the blood-brain barrier [BBB] may influence this effect. An intracerebrally implanted glioma G-26 (G-26) mouse brain-tumor model was developed and used in these studies. Histological characterization of this intracerebrally grown tumor revealed its anaplastic character. The astrocytic origin of G-26 was evidenced by glial fibrillary acidic protein staining and electron microscopic visualization of glial filaments. A study of tumor progression and animal survival showed development of a well defined tumor nodule within approximately seven days after the implantation. The median animal survival time was 27 +/- 3.8 days. The integrity of the blood-brain barrier [BBB] within the tumor was evaluated by the intravenous injection of horseradish peroxidase at days 3, 7, 10 and 20 after brain tumor implant and compared to 'sham' controls. The tumor-induced BBB alteration was progressive from day 3 to day 20. Glioma-26 subcutaneously passed in C57BL/6 mice was also continuously cultured in vitro. Its proliferation was inhibited by homologous mouse interferon alpha/beta [MuIFN alpha/beta] but not by human interferon alpha lymphoblastoid or human interferon beta. The in vivo studies of G-26 glioma treatment with MuIFN alpha/beta were performed using single bolus of IFN in osmotically altered animals or slow IFN infusion through osmotic micro-pumps. The slow infusion of IFN had no effect on animal survival. However, a statistically significant increase in animal survival was observed after single bolus IFN treatment following osmotic BBB alteration.
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PMID:Evaluation of blood-brain barrier permeability and the effect of interferon in mouse glioma model. 128 Dec 26

Nine patients with a recurrent malignant glioma were treated with repeated intracavitary or intracerebroventricular injections of human recombinant interleukin-2 (rIL-2) alone or in combination with systemic interferon-alpha (IFN-alpha). Five patients received only rIL-2 and four were treated with rIL-2 plus subcutaneous injections of IFN-alpha. Therapy was administered on a Monday, Wednesday, Friday schedule for up to 10 weeks, beginning with a dose of 10,000 IU rIL-2/injection. Doses were escalated every two weeks until some toxicity was apparent. The maximum amount of rIL-2 any one patient in this group received was 580,000 IU. Patients on combination immunotherapy were held at an rIL-2 dosage of 10,000 IU while IFN-alpha, which began at 3 million IU, was escalated every other week up to 18 million IU/dose. They were then held at that IFN-alpha dosage and rIL-2 was increased to 50,000 IU. The total amount of rIL-2 and IFN-alpha any one in this group received was 510,000 IU and 417 million IU, respectively. Repeated injections of 10,000 IU rIL-2 were well-tolerated by all nine patients and no change in their functional status was seen. At doses at 50,000 IU rIL-2, increased edema around the tumor cavity was observed by MRI/CT scand in 3/5 patients and clinical side-effects in the form of somnolence and headache along with some morbidity specifically associated with tumor location were also seen. Patients receiving rIL-2+ IFN-alpha showed progressive fatigue, muscle weakness, and occasionally nausea. Two of these patients showed increased peritumoral edema on MRI/CT scan.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment of recurrent malignant glioma by repeated intracerebral injections of human recombinant interleukin-2 alone or in combination with systemic interferon-alpha. Results of a phase I clinical trial. 154 81

Previous studies have suggested that structural abnormalities involving the short arm of chromosome 9 are frequently associated with gliomas. The alpha-, beta-, and omega-interferon (IFNA, IFNB1, and IFNW, respectively) and the methylthioadenosine phosphorylase (MTAP) genes have been mapped to the short arm of chromosome 9, band p22. Homozygous deletions of these genes have been reported in many leukemia- and glioma-derived cell lines. In this report, we present a detailed analysis of partial and complete homozygous or hemizygous deletions of DNA sequences on 9p in human cell lines and primary tumor samples of glioma patients. Ten of 15 (67%) glioma-derived cell lines had hemizygous or homozygous deletion of IFN genes or rearrangement of sequences around these genes, while 13 of 35 (37%) primary glioma tumor samples had hemizygous (8 tumors) or homozygous (5 tumors) deletion of the IFN genes. The shortest region of overlap of these deletions maps in the interval between the centromeric end of the IFN gene cluster and the MTAP gene. In the cell lines and primary tumors examined, these gross genomic alterations were seen only in association with high grade or recurrent gliomas. Our observations confirm that loss of DNA sequences on 9p, particularly the IFN genes, occurs at a significant frequency in gliomas, and may represent an important step in the progression of these tumors. These results are consistent with a model of tumorigenesis in which the development or progression of cancer involves the loss or inactivation of a gene or several genes that normally act to suppress tumorigenesis. One such gene may be located on 9p; this gene may be closely linked to the IFN genes. Nevertheless, loss of the IFN genes, when it occurs, may play an additional role in the progression of these tumors.
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PMID:Molecular analysis of deletions of the short arm of chromosome 9 in human gliomas. 156 21

Dosage and schedules for the treatment of malignant glial tumors using IFN (interferon) are still uncertain and controversial. In this study we give the preliminary results of treatment in 28 patients with glioblastoma multiforme (GBM). 6 patients were treated with local injection of beta-IFN through an Ommaya reservoir; 4 patients with beta-IFN followed by systemic chemotherapy (Cisplatin + Etoposide), and 18 patients with chemotherapy only. Two end points were evaluated: 1) Whether or not the patients responded to treatment. 2) Length of Time to Tumor Progression (TTP) after surgery. We found that IFN alone was ineffective. Results were improved when local immunotherapy was associated with systemic chemotherapy. New drugs and investigation of possible pharmacological synergism are needed.
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PMID:Local immunotherapy (beta-IFN) and systemic chemotherapy in primary glial tumors. 164 48

Doses and schedules for treatment of malignant glial tumors, using IFN are still uncertain and controversial. In this study preliminary results of treatment of 10 glioblastoma multiforme patients are shown. Six patients were treated with local injection of beta-IFN through an Ommaya reservoir: 4 with beta-IFN followed by systemic chemotherapy (CDDP-VP16); we found that IFN alone was ineffective. Results were improved when local immunotherapy was associated with systemic chemotherapy. New drugs and investigation of possible pharmacological synergism are needed.
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PMID:Intratumoral beta interferon and systemic chemotherapy. Preliminary data in GBM patients. 196 5

The antiproliferative effects of human recombinant interferon-alpha (rIFN-alpha A) and interferon-beta (rIFN-beta ser) were assessed in vitro against seven human glioma cell lines. Further analysis of one of these lines (EFC-2) in response to rIFN-alpha A demonstrated a minimum growth inhibition by day 6 of treatment, whereas a 50% inhibition of cell growth was observed with a dose of 50 U/ml of IFN-beta ser. No significant growth inhibition was seen by rIFN-alpha A at doses up to 500 U/ml. Addition of rIFN-alpha A to rIFN-beta ser-treated EFC-2 cells neither suppressed nor augmented the antiproliferative response to IFN-beta ser. The binding of 125I-labeled rIFN-alpha A or 125I-labeled rIFN-beta ser to EFC-2 cells was inhibited competitively by increasing concentrations of either unlabeled rIFN-alpha A or rIFN-beta ser. This suggests that the cellular receptors for both rIFN-alpha A and rIFN-beta ser appear to be intact and appear to bind both agents equally. Furthermore, incubation of EFC-2 cells for 72 h with either rIFN-alpha A or rIFN-beta ser resulted in an increase in 2',5'-oligoadenylate (2-5A) synthetase activity 5-fold with rIFN-alpha A and 50-fold with rIFN-beta ser. Similarly, the 68-kD IFN-induced protein kinase was induced substantially with rIFN-beta ser but only slightly induced with rIFN-alpha A treatment. These results suggest that EFC-2 human glioma cells demonstrate a differential sensitivity in terms of growth inhibition to rIFN-beta ser and to rIFN-alpha A which appears to correlate with a differential induction of both intracellular 2-5A synthetase and protein kinase activity. These results cannot be explained solely on the basis of surface receptor binding of rIFN-alpha A and rIFN-beta ser. These data do suggest that, for human glioma cells in culture, type I IFN receptors may display a subtle architectural variation that allows equivalent binding of both IFN-alpha and IFN-beta ser, but allows an enhanced signal transduction and biological effect only after binding a specific IFN subtype.
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PMID:Growth inhibitory effects of interferon-beta but not interferon-alpha on human glioma cells: correlation of receptor binding, 2',5'-oligoadenylate synthetase and protein kinase activity. 214 Mar 95

In summary, many actual interactions between tumors in the CNS and the immune system have been demonstrated. The normal brain does not possess a lymphatic system and is partially hidden from the systemic immune system by the BBB, furthermore brain cells do not express MHC antigens which are necessary for the initiation of an immune response. In pathological conditions however, immunocompetent cells may find their way through transformed endothelial cells. Microglia and astrocytes may function as antigen presenting cells. Glioma cells when stimulated by cytokines such as IFN gamma can be induced to express MHC class I and class II antigens, thus making them more susceptible to an immune attack. In addition glioma cells are capable of secreting several cytokines including IL 1, IL 3 and IL 6 also involved in the generation of an immune response. Indeed, a functional analysis of lymphocytes infiltrating gliomas has revealed the accumulation at the tumor site of cytotoxic T lymphocytes as well as NK cells. However host-immune responses against gliomas seem to be weak in comparison to other cancers. Glioma cells are known to secrete TGF beta 2 and PGE 2 which may in part be responsible for this lack of immune response, thus shielding themselves from immune attack. In order to be recognized by the immune system the tumor cells must express TAA in addition to MHC antigens, and such TAA have been identified by MAbs. These MAbs can be used for "targeted" therapy when coupled to toxic agents or radionuclides. Preclinical studies have shown that, after intravenous or intracarotid injection, there is specific accumulation of the MAb in the tumor but in insufficient amounts for therapeutic use. The relatively small amount of MAb binding to the tumor in vivo can be due to several factors: not all the cells in a single tumor express a given tumor-associated antigens, the MAb may have a low affinity for the antigen, the BBB may hinder the passage of the MAb. Attempts have been made to overcome these drawbacks by opening the BBB for example. In addition MAbs can readily be used for the treatment of carcinomatous meningitis. There has been little success in the development of immunotherapy with IFN beta 1 and even less with adoptive immunotherapy using LAK cells plus IL 2. TIL as well as LAK cells can be expanded in vitro with IL2 and it is feasible to reinject these cells into the tumor site.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Immunobiology of brain tumors. 218 Apr 10

Recent studies have suggested that astrocytes share with the macrophages several properties in vitro, among which is the ability to express MHC Class II molecules and to present some antigens to syngeneic primed lymphocytes (MHC-restricted presentation). It has been claimed in the literature that astrocytes cannot start the presentation and cannot express the related MHC Class II molecules if not previously stimulated with gamma IFN. In this paper we report that 2 human GFAP + glioma cell lines, incubated in culture with various soluble antigens for at least 24 h, were able, in the absence of gamma IFN or of activated lymphocytes, to express the MHC Class II and to expose the antigens on their surfaces. Moreover, when a lysosomotropic agent such as chloroquine was added during the incubation, no MHC Class II expression was observed. This last datum suggests that in astrocytes, as is already known in macrophages, the processing of antigens and their assembling with MHC Class II molecules probably involves the lysosomal apparatus.
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PMID:MHC class II expression by human glioma cells after in vitro incubation with soluble antigens. 235 71

Neuroblastoma cell lines can have very low MHC Ag expression. The cell lines are insensitive to allo-killing by primed CTL, but are sensitive to non-MHC-restricted cytotoxicity. IFN-gamma increased class I expression, but the cells remained insensitive to CTL. Susceptibility to nonrestricted effectors was preserved. Class I+ glioma cell lines behaved similarly. The CTL resistance was localized to the recognition phase. Neuroblastoma lines did not form conjugates with primed T cells, but were lysed if they were coupled to the effectors via lectins. The levels of class I expression, and resistance to CTL, were constant over a range of IFN doses. HLA-A,B,C structure and distribution were studied more intensively on one cell line, CHP-100. HLA-A2 and -A3 were present on greater than or equal to 99% of the cells, in a unimodal distribution. After IFN treatment, the levels were similar to B cell controls. In two-dimensional gel electrophoresis, the molecules co-migrated with those of B cell controls. The defect may thus be in accessory proteins that are necessary for T cell recognition or binding, rather than in the structure or distribution of the HLA-A,B,C proteins.
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PMID:IFN-treated neuroblastoma cell lines remain resistant to T cell-mediated allo-killing, and susceptible to non-MHC-restricted cytotoxicity. 245 35

The combined effects of Acyclovir [9-(2'-hydroxyethoxymethyl)guanine; ACV] and human interferon-alpha (IFN-alpha) on replication of the herpes simplex virus type I (HSV-1) were determined in human neural cell lines, neuroblastoma (IMR), glioblastoma (118MGC), and glioma (U251MG). HSV-1 grew well in all these cells, with final yields of more than 1 x 10(6) PFU/ml. In terms of virus-yield reduction, ACV was found to be highly effective in IMR, moderately effective in U251MG, but ineffective in 118MGC. By contrast, IFN-alpha reduced the virus yield significantly in 118MGC and in U251MG, but did not in IMR. Combined application of ACV and IFN-alpha strongly inhibited the virus replication in all three cell lines with various degrees of synergism or additive effect. These results were also confirmed by immunofluorescent examinations. The sensitivity of HSV-1 to ACV or IFN-alpha was found to be different among the three different cell types. By combining the two agents, the virus growth was strongly suppressed in all the cells. These results suggest the importance of combination therapy for severe type of herpes simplex encephalitis in clinical practice.
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PMID:Combined effects of acyclovir and human interferon-alpha on herpes simplex virus replication in cultured neural cells. 255 47


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