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PubMed1992

[Experimental studies on the antitumor activity of glioma-infiltrating lymphocytes against autologous glioma].

In the present study, antitumor activity of glioma-infiltrating lymphocytes (GILs) was compared to that of lymphokine-activated killer (LAK) cells. Results suggested that killing activity of GILs against autologous glioma cells was significantly higher than that of LAK cells (P less than 0.05), but their activity against allogeneic glioma cells was not different from that of LAK cells (P greater than 0.05). Analysis of cell surface phenotypes showed that CD4+ cells were a main portion of LAK cells, and CD8+ were predominant in the GILs. In the beginning, growth of GILs was slower than that of LAK cells. As time went on, generation of GILs was faster than that of LAK cells. The results suggested that GILs were superior to LAK cells for adoptive immunotherapy in patients with brain glioma.

Brain Neoplasms↗
PubMed2005

Tyrosine phosphorylation of PYK2 mediates heregulin-induced glioma invasion: novel heregulin/HER3-stimulated signaling pathway in glioma.

Receptor tyrosine kinases of the EGFR family transmit extracellular signals that control diverse cellular functions such as proliferation, differentiation and survival. Signaling function of a member of this family, HER3, is believed to be impaired due to deviations in its kinase consensus motifs. Here we address the functional role and signaling mechanisms of HER3. HER3 preferentially forms heterodimers with HER2 inducing the most potent mitogenic signal among EGFR family members. Our data show that in a glioma-derived cell line the cytoplasmic tyrosine kinase PYK2 is constitutively associated with HER3 and that stimulation with Heregulin results in PYK2 tyrosine phosphorylation. HER3, but not HER2, mediates the phosphorylation of the C-terminal region of PYK2 to promote a mitogenic response through activation of the MAPK pathway. A central role of PYK2 in signaling downstream of HER3 is substantiated by the demonstration that expression of a dominant-negative PYK2-KM construct abrogates the Heregulin-induced MAPK activity and inhibits the invasive potential of glioma cells. These results suggest a novel Heregulin/HER3-stimulated signaling pathway in glioblastoma-derived cell lines that involves phosphorylation of PYK2 and mediates invasiveness of glioma cells.

Focal Adhesion Kinase 2↗
PubMed2003

A thrombin inhibitor reduces brain edema, glioma mass and neurological deficits in a rat glioma model.

Although thrombin is a critical enzyme in the coagulation cascade, it has become apparent that it has many other effects. Thus, it may induce brain edema formation, angiogenesis and cell proliferation. Because of the importance of these three factors in the extremely poor prognosis of glioma patients, the present study examined the role of thrombin in that disease state. We found that thrombin activity is increased in a rat glioma model and thrombin positive cells were present in the tumor. Anti-thrombin treatment with argatroban reduced brain edema, tumor growth, and tumor-related neurological deficits. Our results suggest that thrombin is a new target for glioma treatment.

Animals↗
PubMed1990

Radioimmunoassay of glioma-associated antigen in cerebrospinal fluid and its usefulness for the diagnosis and monitoring of human glioma.

Quantitative determination of human glioma-associated antigen in cerebrospinal fluids (CSFs) obtained from 66 patients with a variety of neurological diseases was performed by solid-phase radioimmunoassay with a monoclonal antibody (G-22). In this system, the minimum detectable amount of the antigen in the CSF was 8 ng/ml. It was demonstrated that CSF diagnosis of glioblastoma might be possible in the case of small tumors with a diameter of less than 2 cm. CSFs obtained from all 18 patients with glioma were positive and the level varied from 11.2 to 186.1 ng/ml. The antigen level in the cystic fluid of the tumor was higher than that in CSF. There was a tendency for the antigen level in CSF to be correlated with the tumor size and the type of histology. The malignant types of glioblastoma or medulloblastoma showed higher levels than the benign type of ependymoma and astrocytoma. Most types of non-gliomatous brain tumor were negative except immature teratoma, meningioma with central neurofibromatosis, and metastatic brain tumor from lung cancer. We also noted that tumor progression or regression of malignant glioma could be predicted by the monitoring of the antigen in the CSF.

Adult↗
PubMed1994

Glioma-stimulated chemoattraction of endothelial cells and fibroblasts in vitro: a model for the study of glioma-induced angiogenesis.

Induction of angiogenesis is essential for the continued growth of solid tumors, and one critical component of tumor-induced angiogenesis involves the stimulation of microvascular cells to migrate into the growing mass. We have developed a convenient model system utilizing dual co-culture chambers to study cellular chemotaxis induced by glioma cells in vitro. In this system, rat C6 glioma cells induced migration of fibroblasts and brain capillary endothelial cells. The migratory response was directly related to the number of C6 cells serving as stimulus in the lower chamber. Similar migratory responses were induced by C6 cell conditioned medium in a concentration dependent fashion. Medium conditioned by cultured human anaplastic astrocytoma cells was also found to contain potent chemotactic factor(s). This system may ultimately be employed in the identification of particular glioma cell population(s) and secreted factor(s) responsible for the chemoattraction of microvascular cells.

Cell Movement↗
PubMed2000

Immunohistochemical analysis of glioma-infiltrating leucocytes after peripheral therapeutic immunization with interferon-gamma-transfected glioma cells.

We have shown previously that rejection of preinduced rat brain tumours is possible following therapeutic immunizations with interferon-gamma (IFN gamma)-transfected glioma cells (N32-IFN gamma). In the present study we have used the same model to evaluate whether quantitative differences in tumour-infiltrating lymphocytes can be detected between animals receiving therapeutic immunizations with either IFN gamma-transfected glioma cells, wild-type glioma cells or no treatment. Since leucocyte transpedesis into the tumour can be anticipated to depend on the state of vascularization, we have mapped the development of microvessels in the tumour in parallel with the leucocyte infiltration. Our results show that microvessels start to form at day 7 and then gradually increase in number and size, indicating the establishment of an extensive vascularization by day 24. Leucocyte infiltration displays a biphasic pattern after tumour grafting. We have therefore studied the infiltration kinetics after an early immunization (1 day after intracerebral isografting) and compared the effects with those of a late immunization (10 days after intracerebral isografting) with N32-IFN gamma or wild-type N32. Our results show (1) an early infiltration of granulocytes 3 days after isografting; (2) a T-cell-receptor-positive (TCR+) T-cell infiltration starting on day 10; (3) a macrophage infiltration starting on day 13; (4) a CD8+ cell infiltration starting on day 13. The proportions of TCR+ T cells, CD8+ cells and natural killer cells differs significantly between animals immunized with N32-IFN gamma and those receiving wild-type N32, when analysed 14 days after immunization at day 10. This difference can only be detected when animals are immunized at later stages of tumour growth. We propose that this could depend on an early-immunization-independent leucocyte infiltration during tumour establishment. This has to be considered when evaluating studies of leucocyte infiltration in experimental tumours.

Animals↗
PubMed2006

Temozolomide after radiotherapy for newly diagnosed high-grade glioma and unfavorable low-grade glioma in children.

Chemotherapy is commonly used in the treatment of children with high-grade glioma, although its usefulness is uncertain. We conducted a multi-institutional study to evaluate the efficacy of temozolomide given after radiotherapy in children with newly diagnosed high-grade glioma and unfavorable low-grade glioma (gliomatosis cerebri or bithalamic involvement). Optional window therapy of intravenous irinotecan (10 doses of 20 mg/m2 per cycle x 2) was given over 6 weeks. The 5-day schedule of temozolomide (200 mg/m2 per day) started 4 weeks after the completion of radiotherapy and continued for a total of 6 cycles. Thirty-one eligible patients (median age: 12.3 years) participated. Tumors most commonly involved cerebral hemispheres (n = 13, 42%) and thalamus (n = 14, 45%). Whereas six patients underwent radical resection, the remainder had limited surgery, including biopsy (n = 14, 45%). The predominant histologic diagnoses were glioblastoma multiforme (n = 15, 48%) and anaplastic astrocytoma (n = 10, 32%). Two patients had bithalamic grade II astrocytoma. Twenty-seven patients received radiotherapy (median dose: 59.4 Gy), including craniospinal irradiation in 3 because of leptomeningeal spread. Four patients did not receive radiotherapy in this study because of consent withdrawn (n = 2), toxicity during window therapy (n = 1), or at the physician's discretion (n = 1). Twenty-three patients received 112 cycles of temozolomide therapy. The 2-year progression-free and overall survival estimates were 11 +/- 5% and 21 +/- 7%, respectively. Although the heterogeneity of prognostic factors in our patients made assessment of treatment outcome more difficult, the addition of 6 cycles of temozolomide after radiotherapy did not seem to alter the poor outcome of these patients.

Adolescent↗
PubMed1987

Comparative localization of glioma-reactive monoclonal antibodies in vivo in an athymic mouse human glioma xenograft model.

Radioiodinated murine monoclonal antibodies (Mabs) 81C6, Me 1-14, C12, D12, and E9, made against or reactive with human gliomas but not normal brain, and Mab UJ13A, a pan-neuroectodermal Mab reactive with normal human glial and neural cells, were evaluated in paired label studies in the D-54 MG subcutaneous human glioma xenograft model system in nude mice. Following intravenous injection in the tail vein of mice bearing 200-400 mm3 tumors, specific localization of Mabs to tumor over time (6 h-9 days) was evaluated by tissue counting; each Mab demonstrated a unique localization profile. The comparison of localization indices (LI), determined as a ratio of tissue level of Mab to control immunoglobulin with simultaneous correction for blood levels of each, showed Mabs 81C6 and Me 1-14 to steadily accumulate in glioma xenografts, maintaining LI from 5-20 at 7-9 days after Mab injection. Mab UJ13A peaked at day 1, maintaining this level through day 2, and declining thereafter. Mabs D12 and C12 peaked at days 3 and 4, respectively, and E9 maintained an LI of greater than 3 from days 3-9. Percent injected dose localized/g of tumor varied from a peak high of 16% (81C6) to a low of 5% (Me 1-14 and UJ13A). Immunoperoxidase histochemistry, performed with each Mab on a battery of primary human brain neoplasms, revealed that Mabs 81C6 and E9, which demonstrated the highest levels of percent injected dose localized/g of tumor over time, reacted with antigens expressed in the extracellular matrix. This finding suggests that extracellular matrix localization of antigen represents a biologically significant factor affecting localization and/or binding in the xenograft model used. The demonstration of significant localization, varied kinetics and patterns of localization of this localizing Mab panel warrants their continued investigation as potential imaging and therapeutic agents for human trials.

Animals↗
PubMed2004

Inflammatory and anti-glioma effects of an adenovirus expressing human soluble Fms-like tyrosine kinase 3 ligand (hsFlt3L): treatment with hsFlt3L inhibits intracranial glioma progression.

Glioblastoma multiforme is an intracranial tumor that has very poor prognosis. Patients usually succumb to their disease 6 to 12 months after they are diagnosed despite very aggressive treatment modalities. We tested the efficacy of a potent differentiation and proliferation factor for the professional antigen-presenting dendritic cells (DCs), i.e., Flt3L, for its potential role as a novel therapy for gliomas. We investigated the ability of recombinant adenoviral vectors encoding human soluble Flt3L (hsFlt3L) to improve the survival of Lewis rats bearing intracranial syngeneic CNS-1 gliomas. We show that RAdhsFlt3L can improve survival in a dose-dependent manner. Seventy percent of rats survive when treated with 8 x 10(7) pfu RAdhsFlt3L (P < 0.0005). In addition we demonstrate in both naive Lewis rats and C57BL/6 mice the presence of increased numbers of cells bearing DC markers (OX62 and MHCII, in rats, or CD11C, 33D1, MHCII, and F4/80, but not DEC205, in mice) in sites of brain delivery of RAdhsFlt3L. These results show that expression of hsFlt3L in the brain leads to the presence of cells displaying DC markers. We demonstrate that treatment with hsFlt3L leads to inhibition of tumor growth and significantly increased life span of animals implanted with syngeneic CNS-1 glioma cells. Animals that had survived for long periods, i.e., 6 months, had eliminated the implanted tumors after neuropathological analysis; on the other hand, some of the 3-month survivors still appeared to harbor brain tumors. Our results have profound implications for immune-mediated brain tumor therapy and also suggest the ability to recruit DC-like cells within the brain parenchyma in response to the local expression of Flt3L from adenoviral vectors.

Adenoviridae↗
PubMed1977

Alanine inhibition of pyruvate kinase in gliomas and meningiomas. A diagnostic tool in surgery for gliomas?

In gliomas a shift was found in the composition of enzymes, manifested by abnormal inhibition of pyruvate kinase by alanine. This study demonstrates the appearance of the MII-type isoenzyme in various gliomas. This MII type is also found in meningiomas but not in normal brain tissue. The method of enzyme examination described may be valuable as a diagnostic aid in the surgery of gliomas.

Alanine↗
PubMedDate not supplied

Preproenkephalin mRNA in neuroblastoma X glioma, NG 108-15, hybrid cells and in parental cell lines: mouse neuroblastoma, N18, and rat glioma, C6.

Preproenkephalin mRNA was analyzed in Neuroblastoma X Glioma, NG 108-15, cells as well as in respective parental cell lines, i.e. mouse Neuroblastoma N18 and rat Glioma C6, using a rat preproenkephalin cDNA as a probe. NG synthesize efficiently a preproenkephalin mRNA, similar in size to that of normal tissues. Of the two parental cell lines, Neuroblastoma seems to synthesize it as well as NG; conversely Glioma cell lines under the same conditions do not appear to synthesize preproenkephalin mRNA with the same efficiency as NG and N18.

Animals↗
PubMed2001

Magnetic resonance imaging of ethyl-nitrosourea-induced rat gliomas: a model for experimental therapeutics of low-grade gliomas.

Human low-grade gliomas represent a population of brain tumors that remain a therapeutic challenge. Preclinical evaluation of agents, to test their preventive or therapeutic efficacy in these tumors, requires the use of animal models. Spontaneous gliomas develop in models of chemically induced carcinogenesis, such as in the transplacental N-ethyl-N-nitrosourea (ENU) rat model. However, without the ability to detect initial tumor formation, multiplicity or to measure growth rates, it is difficult to test compounds for their interventional or preventional capabilities. In this study Fisher-334 rats, treated transplacentally with ENU, underwent magnetic resonance imaging (MRI) examination in order to evaluate this approach for detection of tumor formation and growth. ENU-induced intracranial cerebral tumors were first observable in T2-weighted images beginning at 4 months of age and grew with a mean doubling time of 0.487 +/- 0.112 months. These tumors were found histologically to be predominately mixed gliomas. Two therapeutic interventions were evaluated using MRI, vitamin A (all-trans retinol palmitate, RP), as a chemopreventative agent and the anti-angiogenic drug SU-5416. RP was found to significantly delay the time to first tumor observation by one month (P = 0.05). No differences in rates of tumor formation or growth rates were observed between control and RP-treated groups. MRI studies of rats treated with SU-5416 resulted in reduction in tumor growth rates compared to matched controls. These results show that MRI can be used to provide novel information relating to the therapeutic efficacy of agents against the ENU-induced tumor model.

Angiogenesis Inhibitors↗
PubMed2001

AT1 receptor is present in glioma cells; its blockage reduces the growth of rat glioma.

Malignancy of neoplasms is partly dependent on angiogenesis. Angiotensin II mediates angiogenesis and transcription of growth-related factors through stimulation of the AT1 receptor (AT1R). Losartan, a drug used mostly for treatment of hypertension, binds strongly to this receptor. We found the presence of AT1 receptor on C6 glioma cells and studied the effect of Losartan on the growth and angiogenesis of C6 rat glioma; Losartan in dose of 80 mg/kg induced 79% reduction of tumoural volume with a significant decrease of vascular density, mitotic index and cell proliferation. Our results demonstrate the conspicuous presence of AT1R in malignant glial cells and a favourable therapeutic response in experimental glioma by selective blockage of the AT1 receptor.

Angiotensin II↗
PubMedDate not supplied

Low grade chiasmatic-hypothalamic glioma-carboplatin and vincristin chemotherapy effectively defers radiotherapy within a comprehensive treatment strategy -- report from the multicenter treatment study for children and adolescents with a low grade glioma -- HIT-LGG 1996 -- of the Society of Pediatric Oncology and Hematology (GPOH).

BACKGROUND: Low grade gliomas arise in all CNS-locations and age groups, chiasmatic-hypothalamic tumors occur especially in young children. Early radiotherapy (RT) shall be deferred by chemotherapy (CT) within the concept of the HIT-LGG 1996 study, offering a comprehensive treatment strategy for all age groups. PATIENTS: 198 of 905 protocol patients (21.9 %) had a chiasmatic (34), chiasmatic-hypothalamic (144) or hypothalamic (20) primary tumor, median age at diagnosis 3.6 years (0.2-16.3 y.), 54 had neurofibromatosis (27.3 %), 108 female (54.5 %). 98 children had severe visual impairment as their first symptom. The initial neurosurgical intervention resulted in 5 complete, 26 subtotal, 45 partial resections, 67 biopsies; 55 children had a diagnosis on the basis of neuroradiologic findings. Histology showed 132 pilocytic astrocytoma I degrees , 6 astrocytoma II degrees /nos and 2 DIGG/DIA I degrees (3 not known). RESULTS: 82 children were treated at diagnosis, 68 upon clinical or radiological progression following observation times of 3.0 to 115.0 months. RT: 27 children received conventional (18) or interstitial (8) RT (1 not documented) at a median age of 7.3 years; 7 tumors went into further progression. At a median observation time of 50.1 months 21 tumors are stable, 3 regressive (2 not evaluable, 1 death). CT: 123 children received vincristin/carboplatin at a median age of 3.7 years. 105/123 achieved CR/PR/SD. 44/123 tumors were progressive after median 22.5 months, 37 with a chiasmatic-hypothalamic primary, 16/44 were irradiated. At a median observation time of 44.7 months 2 children are in complete remission, 92 tumors are stable, 8 regressive, 9 progressive. 4 children died, 8 are not evaluable. At 60 months overall survival of the cohort is 0.93; PFS of the CT-group is 0.61, the RT-free survival 0.83. Within the CT-group children with an age at diagnosis < 1 year and non-pilocytic histology are at increased risk for early progression. Causative factors cannot be defined, yet. CONCLUSION: Within the comprehensive treatment strategy for low grade glioma HIT-LGG 1996 chemotherapy is effective to delay the need for early radiotherapy in chiasmatic-hypothalamic glioma. More effective reduction of the risk for progression has to be sought for young children < 1 year.

Adolescent↗
PubMed2002

Avian retrovirus infection causes naturally occurring glioma: isolation and transmission of a virus from so-called fowl glioma.

So-called fowl glioma is characterized by multiple nodular gliomatous growths associated with disseminated non-suppurative encephalitis. To investigate the possibility of the induction of the gliomatous lesions, chicks of Japanese bantams (Gallus gallus domesticus) and specific pathogen free chickens (C/O strain White Leghorn) were intracerebrally inoculated with a brain homogenate or culture supernatant from a bantam affected with fowl glioma. All bantams and 16 chickens (89%) in the inoculated groups showed non-suppurative encephalitis, and the 18 bantams (82%) and five chickens (28%) developed multiple nodules consisting of aggregations of astrocytes in the cerebrum. These astrocytes had avian leukosis virus (ALV) antigen. By Southern blot analysis, the ALV sequence was detected both in DNA prepared from the brains of the inoculated birds and in DNA from the inoculum. Ultrastructurally, tadpole-shaped particles, approximately 100 nm in diameter, were detected in the concentrated supernatant of the chicken embryo fibroblasts, and budding of the particles was noted. These results substantiated that fowl glioma of the bantams could be transmitted by intracerebral inoculation of the affected tissue and that the causal agent was an unidentified strain of ALV.

Animals↗
PubMed1995

Mannose-binding protein recognizes glioma cells: in vitro analysis of complement activation on glioma cells via the lectin pathway.

The lectin pathway is a novel pathway for activation of the complement cascade, which is initiated by the binding of mannose-binding protein (MBP) to its carbohydrate ligands. We investigated whether the complement system was activated in vitro by glioma cells through this pathway to the C3 level. MBP was found to bind to all six glioma cell lines tested by using flow cytometric analysis. Binding of a complex of MBP-associated serine protease and MBP was observed in two of the cell lines examined, thereby resulting in C4 consumption. Activation of C3 was hemolytically evaluated in these two lines. C3 consumption was also observed in one. Based on these results, it is likely that recognition by MBP followed by complement activation occurs in certain glioma cell lines.

Carrier Proteins↗
PubMed1986

Detection of human glioma-associated antigen by rat monoclonal antibody raised against syngeneic rat glioma cells.

A monoclonal antibody termed "FR77" was obtained from a hybridoma clone established by fusion between P3x63Ag8.653 mouse myeloma cells and spleen cells of a Fischer F344 rat hyperimmune to syngeneic 9L/R3 glioma cells. Immunoperoxidase staining of various cultured cells showed that FR77 was reactive to both rat and human glioma cells, but was not reactive with other nonglioma cells. Immunohistochemical examination of paraffin-embedded or cryostat-frozen sections of various human tissues revealed that FR77 was strongly reactive with glioblastoma, grade III astrocytoma, and craniopharyngioma; partially reactive with intracerebral primitive neuroectodermal tumor, pineoblastoma, and desmoplastic medulloblastoma; and weakly reactive with low-grade astrocytoma. It was not reactive with other types of brain tumors and normal human tissues tested. The FR77-defined antigen was observed to be predominantly localized in the cytoplasm of antigen-bearing cells as suggested by the immunostaining pattern, but part of it was also expressed on the cell surface of glioma cells as demonstrated by a complement-mediated cytotoxic test. Fractionation of the antigenic component and periodic acid treatment of tumor tissue bearing the FR77-defined antigen indicated that the antigen is of a neutral glycolipid nature and that the antigenic determinant to FR77 is present on its sugar portion.

Animals↗
PubMed1998

A novel approach to glioma gene therapy: down-regulation of the vascular endothelial growth factor in glioma cells using ribozymes.

Glioblastoma multiforme is one of the most highly vascularized solid neoplasms, therefore treatments that target neovascularization process would be of great clinical importance. Studies of glioblastoma angiogenesis have revealed that expression of the vascular endothelial growth factor (VEGF) is up-regulated in these tumors. Previous reports have shown that down-regulation of VEGF correlates with modification in the glioma growth. To examine this phenomenon further, in this study we constructed two hammerhead ribozymes (RZI and RZII) to target the 5' common region of VEGF mRNA. Both ribozymes exhibited site-specific cleavage to a 318-nucleotide VEGF transcript and showed a high digestion efficiency in vitro (65-95%). After the transfection of glioma cells with two expression vectors carrying the ribozyme sequence, Northern blot analyses detected high levels of ribozyme expression. Treatment of the glioma cells with the ribozymes resulted in a reduction in VEGF mRNA in six of eight clones. Furthermore, the anti-VEGF effect was confirmed at protein level. Thus, enzyme-linked immunoabsorbent analyses (ELISA) showed a >70% reduction in the VEGF165 expression level. These results indicate that hammerhead ribozymes may be useful in down-regulating VEGF expression and suggest that anti-VEGF strategies may be used to potentiate other gene therapies targeting tumor suppressor genes.

Blotting, Northern↗