Capillary permeability factor secreted by malignant brain tumor

1990 ◽  
Vol 72 (2) ◽  
pp. 245-251 ◽  
Author(s):  
Takanori Ohnishi ◽  
Peter B. Sher ◽  
Jerome B. Posner ◽  
William R. Shapiro
Keyword(s):  
Tumor Cells ◽  
Capillary Permeability ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Lipoxygenase Inhibitor ◽  
Brain Capillary ◽  
Content Type ◽  
Rat Glioma ◽  
Permeability Factor ◽  
Capillary Endothelial Cells

✓ Conditioned media from two human malignant gliomas, C6 rat glioma, Walker 256 carcinosarcoma, and normal human glia were concentrated 50-fold to create a culture supernatant (SUP-C). The effect of SUP-C on rat brain capillary permeability was investigated by measuring the entry of 14C-aminoisobutyric acid (14C-AIB) by means of quantitative autoradiography. The SUP-C contained proteins with a molecular weight of 10 kD or greater. The SUP-C from all tumor cells markedly increased brain capillary permeability, indicating the presence of a permeability factor, whereas that from normal glial cells did not. Glioma cells produced more factor after incubation for 20 hours than 4 hours. The activity of capillary permeability factor in the SUP-C was inhibited by pretreatment of animals with BW755C (lipoxygenase inhibitor), but not with indomethacin (cyclo-oxygenase inhibitor). Pretreatment of animals with dexamethasone prior to intracerebral infusion of tumor SUP-C significantly reduced the factor-induced increase in capillary permeability. On the other hand, coincubating glioma cells with dexamethasone produced SUP-C with a permeability activity that was about one and a half times greater than that without dexamethasone. These results indicate that glucocorticoids produce their anti-edema effects by directly acting on capillary endothelial cells, possibly through the inhibition of phospholipase A2 activity, resulting in a decrease of lipoxygenase rather than cyclo-oxygenase products. The production of capillary permeability factor by tumor cells was not inhibited, but rather enhanced, by administration of glucocorticoids.

Combined cimetidine and temozolomide, compared with temozolomide alone: significant increases in survival in nude mice bearing U373 human glioblastoma multiforme orthotopic xenografts

2005 ◽  
Vol 102 (4) ◽  
pp. 706-714 ◽  
Author(s):  
Florence Lefranc ◽  
Syril James ◽  
Isabelle Camby ◽  
Jean-François Gaussin ◽  
Francis Darro ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Tumor Cells ◽  
Nude Mice ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Computer Assisted ◽  
Human Glioblastoma ◽  
Content Type ◽  
Human Glioblastoma Multiforme ◽  
Fine Print

Object. Malignant gliomas consist of both heterogeneous proliferating and migrating cell subpopulations, with migrating glioma cells exhibiting less sensitivity to antiproliferative or proapoptotic drugs than proliferative cells. Therefore, the authors combined cimetidine, an antiinflammatory agent already proven to act against migrating epithelial cancer cells, with temozolomide to determine whether the combination induces antitumor activities in experimental orthotopic human gliomas compared with the effects of temozolomide alone. Methods. Cimetidine added to temozolomide compared with temozolomide alone induced survival benefits in nude mice with U373 human glioblastoma multiforme (GBM) cells orthotopically xenografted in the brain. Computer-assisted phase-contrast microscopy analyses of 9L rat and U373 human GBM cells showed that cimetidine significantly decreased the migration levels of these tumor cells in vitro at concentrations at which tumor growth levels were not modified (as revealed on monotetrazolium colorimetric assay). Computer-assisted microscope analyses of neoglycoconjugate-based glycohistochemical staining profiles of 9L gliosarcomas grown in vivo revealed that cimetidine significantly decreased expression levels of endogenous receptors for fucose and, to a lesser extent, for N-acetyl-lactosamine moieties. Endogenous receptors of this specificity are known to play important roles in adhesion and migration processes of brain tumor cells. Conclusions. Cimetidine, acting as an antiadhesive and therefore an antimigratory agent for glioma cells, could be added in complement to the cytotoxic temozolomide compound to combat both migrating and proliferating cells in GBM.

A comparative study on the pharmacokinetics and biodistribution of boronated porphyrin (BOPP) and sulfhydryl boron hydride (BSH) in the RG2 rat glioma model

1995 ◽  
Vol 83 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Crister P. Ceberg ◽  
Arne Brun ◽  
Stephen B. Kahl ◽  
Myoung Seo Koo ◽  
Bertil R. R. Persson ◽  
...  
Keyword(s):  
Body Weight ◽  
Tumor Cells ◽  
Brain Tissue ◽  
Malignant Gliomas ◽  
Normal Brain ◽  
Boron Hydride ◽  
Content Type ◽  
Rat Glioma ◽  
Glioma Model ◽  
Fine Print

✓ Boron neutron capture therapy is a treatment modality for cancer that depends on the specific uptake of boron by the tumor cells. The infiltrative growth of malignant gliomas requires that boron reach and accumulate in migrating cells outside the margin of the tumor; thus, it is important that the biodistribution of new boron compounds is also studied in the surrounding healthy brain tissue. This study is undertaken in the present work, in which the biodistribution and pharmacokinetics of sulfhydryl boron hydride (BSH) and boronated porphyrin (BOPP) in the RG2 rat glioma model are investigated. This model mimics the characteristics of human glioma with cells migrating into the surrounding brain. The animals were infused intravenously with either BSH (25 µg or 175 µg of boron per gram of body weight) or BOPP (12 µg of boron per gram body weight). For the low dose of BSH, the maximum tumor—boron content was 8 ppm at approximately 9 hours after the infusion with a tumor-to-blood ratio of 0.6. At the higher dose, the corresponding figures were 15 ppm after 12 hours with a tumor-to-blood ratio of 0.5. For BOPP, a tumor—boron concentration of 81 ppm was achieved 24 hours after the infusion and sustained in that range for at least 72 hours. The tumor-to-blood ratio at 24 hours was slightly above 6, but continued to increase as the blood was cleared. These results indicate that both compounds are spread into the normal brain tissue following the same pathways as the migrating tumor cells and in this way can be taken up even in distant tumor cell foci.

scholarly journals EXTH-70. ENHANCEMENT OF ANTITUMOR ACTIVITY BY USING 5-ALA–MEDIATED SONODYNAMIC THERAPY TO INDUCE APOPTOSIS AND NECROSIS IN A MOUSE GLIOMA MODEL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi97-vi97
Author(s):  
Satoshi Suehiro ◽  
Takanori Ohnishi ◽  
Akihiro Inoue ◽  
Daisuke Yamashita ◽  
Masahiro Nishikawa ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
High Intensity Focused Ultrasound ◽  
Control Group ◽  
Normal Brain ◽  
Sonodynamic Therapy ◽  
Cytotoxic Effects

Abstract OBJECTIVE High invasiveness of malignant gliomas frequently causes local tumor recurrence. To control such recurrence, novel therapies targeted toward infiltrating glioma cells are required. Here, we examined cytotoxic effects of sonodynamic therapy (SDT) combined with a sonosensitizer, 5-aminolevulinic acid (5-ALA), on malignant gliomas both in vitro and in vivo. METHODS In vitro cytotoxicity of 5-ALA-SDT was evaluated in U87 and U251 glioma cells and in U251Oct-3/4 glioma stemlike cells. Treatment-related apoptosis was analyzed using flow cytometry. Intracellular reactive oxygen species (ROS) were measured and the role of ROS in treatment-related cytotoxicity was examined. Effects of 5-ALA-SDT with high-intensity focused ultrasound (HIFU) on tumor growth, survival of glioma-transplanted mice, and histological features of the mouse brains were investigated. RESULTS The 5-ALA-SDT inhibited cell growth and changed cell morphology. Flow cytometric analysis indicated that 5-ALA-SDT induced apoptotic cell death. The 5-ALA-SDT generated higher ROS than in the control group, and inhibition of ROS generation completely eliminated the cytotoxic effects of 5-ALA-SDT. In the in vivo study, 5-ALA-SDT with HIFU greatly prolonged survival of the tumor-bearing mice compared with that of the control group (p < 0.05). Histologically, 5-ALA-SDT produced mainly necrosis of the tumor tissue in the focus area and induced apoptosis of the tumor cells in the perifocus area around the target of the HIFU-irradiated field. Normal brain tissues around the ultrasonic irradiation field of HIFU remained intact. CONCLUSIONS The 5-ALA-SDT was cytotoxic toward malignant gliomas. Generation of ROS by the SDT was thought to promote apoptosis of glioma cells. The 5-ALA-SDT with HIFU induced tumor necrosis in the focus area and apoptosis in the perifocus area of the HIFU-irradiated field. These results suggest that 5-ALA-SDT with HIFU may present a less invasive and tumor-specific therapy, not only for a tumor mass but also for infiltrating tumor cells in malignant gliomas.

Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had been pulsed with Semliki Forest virus—mediated tumor complementary DNA

2002 ◽  
Vol 97 (5) ◽  
pp. 1184-1190 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Naoki Yajima ◽  
Naoto Tsuchiya ◽  
Junpei Honma ◽  
Ryuichi Tanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Immunity ◽  
Semliki Forest Virus ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Antitumor Effects ◽  
Content Type ◽  
Immunogene Therapy ◽  
Fine Print

Object. Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy. Methods. Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)—mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset—depleted mice and in interferon (IFN) γ—neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored. The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFNγ production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial. Conclusions. Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.

Regional blood flow and capillary permeability in the ethylnitrosourea-induced rat glioma

1981 ◽  
Vol 55 (6) ◽  
pp. 922-928 ◽  
Author(s):  
Kazuo Yamada ◽  
Toru Hayakawa ◽  
Yukitaka Ushio ◽  
Norio Arita ◽  
Amami Kato ◽  
...  
Keyword(s):  
Blood Flow ◽  
Brain Tissue ◽  
Evans Blue ◽  
Capillary Permeability ◽  
Regional Blood Flow ◽  
Blue Staining ◽  
Content Type ◽  
Rat Glioma ◽  
Blood Flows ◽  
Diameter Reduction

✓ Regional cerebral blood flow and capillary permeability of rat brains bearing ethylnitrosourea-induced gliomas of various size were investigated with 14C-antipyrine autoradiography and Evans blue staining. In the small tumors (<2 mm in diameter), blood flow was uniformly reduced when compared to the adjacent brain. Even in tiny tumors (0.3 to 0.4 mm in diameter), reduction in blood flow was evident. In the medium (2 to 4 mm in diameter) and large (> 4 mm in diameter) tumors, the blood flow increased or decreased depending on the part of the tumor examined. The necrotic center and peripheral edge had low blood flows, whereas the viable portion adjacent to the necrotic center had high blood flows. Blood flow in the brain tissue adjacent to medium and large tumors was lower than control brain tissue, probably due to local edema. Leakage of intravenous Evans blue in the tissue was only evident in the large tumors with central necrosis. The present findings suggest that neovascularization of the tumor may occur when the tumor reaches a certain size, and leaky new vessels may be the cause of brain edema associated with tumor.

Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study

2000 ◽  
Vol 92 (5) ◽  
pp. 804-811 ◽  
Author(s):  
Griffith R. Harsh ◽  
Thomas S. Deisboeck ◽  
David N. Louis ◽  
John Hilton ◽  
Michael Colvin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Enzymatic Activity ◽  
Thymidine Kinase ◽  
Tumor Cells ◽  
Malignant Gliomas ◽  
Retroviral Vectors ◽  
Content Type ◽  
Tumor Bed ◽  
Immunohistochemical Evidence ◽  
Fine Print

Object. The gene therapy paradigm of intratumoral activation of ganciclovir (GCV) following transduction of tumor cells by retroviral vectors bearing the thymidine kinase (tk) gene has produced dramatic remissions of malignant gliomas in animal models. In human trials, although the technique has been deemed safe, little antitumor effect has been demonstrated. To evaluate the basis of this inefficacy in human gliomas, the authors conducted a gene-marking trial involving neuropathological and biochemical studies of treated tumor specimens.Methods. Five patients with malignant recurrent gliomas underwent stereotactic biopsy sampling and intratumoral implantation procedures with three aliquots of 106 vector-producing cells (VPCs) in columns. After 5 days, the tumor was resected and the tumor bed reimplanted with VPCs, and a course of GCV was given. Patients received clinical and radiological follow up for 6 months. Tumor specimens were analyzed neuropathologically and for tk gene expression by anti-TK immunohistochemistry and TK enzymatic activity.Four patients tolerated the treatment well but experienced tumor progression. The other developed an abscess after the second operation and died. Increased TK enzymatic activity was demonstrated in the one tumor specimen analyzed. Immunohistochemical evidence of tk gene expression was limited to VPCs. Transduction of tumor cells was not seen. Viable tumor cells were seen near VPCs containing TK. The lymphocytic immune response was mild.Conclusions. Except for the risk of infection inherent in reoperation, this tk—GCV paradigm was both feasible and safe. Pathological studies indicated that limited dissemination of VPCs and vector from the infusion site and failure to transduce tumor cells with the tk gene are major barriers to efficacy.

scholarly journals Effects of the neurogenic cells supernatant on the tumor-inducing ability of glioma 101.8 in rats

2015 ◽  
Vol 3 (1) ◽  
pp. 57-61
Author(s):  
L. Lyubich ◽  
M. Lisyany
Keyword(s):  
Tumor Cells ◽  
Malignant Gliomas ◽  
Clinical Manifestations ◽  
Treatment Strategies ◽  
Glioma Cells ◽  
Intracerebral Injection ◽  
Migration Potential ◽  
The Central Nervous System ◽  
Antitumor Properties ◽  
Brain And Spinal Cord

The use of neurogenic stem cells (NSCs) and neurogenic progenitor cells (NPCs) is one of the areas of brain and spinal cord lesions cell therapy. Intensive research of NSCs biology has revealed their tumor-tropic properties. Great migration potential and integration of NSCs in places of pathology in the central nervous system allows to consider their application as a means of targeted therapy of tumors. Antitumor properties of NSCs substantiate the development of treatment strategies for malignant gliomas using NSCs.The aim was to study the effect of rat neurogenic cells supernatant (NCS) on the tumor-inducing ability of glioma 101.8 cells at the intracerebral implantation in rats.Brain glioma 101.8 was modeling by intracerebral injection of 101.8-glioma cells suspension. NCS was received from whole rat brain tissue on 14th (E14) day of gestation.Modification of 101.8-glioma cells suspension by means of incubation with NCS (0.02 and 0.1 mg/ml) reduced the tumor-inducing ability of tumor cells, postponing the time of tumor clinical manifestations debut and increasing the lifetime of experimental animals.Under conditions of glioma induction with tumor cells, previously modified by NCS, cytotoxic activity of immune cells of tumor-bearing animals in MTT-test with allogeneic 101.8-glioma cells was increased.

scholarly journals Preliminary Report: Rapid Intraoperative Detection of Residual Glioma Cell in Resection Cavity Walls Using a Compact Fluorescence Microscope

2021 ◽  
Vol 10 (22) ◽  
pp. 5375
Author(s):  
Jiro Akimoto ◽  
Shinjiro Fukami ◽  
Megumi Ichikawa ◽  
Kenta Nagai ◽  
Michihiro Kohno
Keyword(s):  
Tumor Cell ◽  
Malignant Glioma ◽  
Tumor Cells ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Fluorescence Microscope ◽  
Talaporfin Sodium ◽  
Surgical Microscope ◽  
Resection Cavity ◽  
Intraoperative Detection

Objective: The surgical eradication of malignant glioma cells is theoretically impossible. Therefore, reducing the number of remaining tumor cells around the brain–tumor interface (BTI) is crucial for achieving satisfactory clinical results. The usefulness of fluorescence–guided resection for the treatment of malignant glioma was recently reported, but the detection of infiltrating tumor cells in the BTI using a surgical microscope is not realistic. Therefore, we have developed an intraoperative rapid fluorescence cytology system, and exploratorily evaluated its clinical feasibility for the management of malignant glioma. Materials and methods: A total of 25 selected patients with malignant glioma (newly diagnosed: 17; recurrent: 8) underwent surgical resection under photodiagnosis using photosensitizer Talaporfin sodium and a semiconductor laser. Intraoperatively, a crush smear preparation was made from a tiny amount of tumor tissue, and the fluorescence emitted upon 620/660 nm excitation was evaluated rapidly using a compact fluorescence microscope in the operating theater. Results: Fluorescence intensities of tumor tissues measured using a surgical microscope correlated with the tumor cell densities of tissues evaluated by measuring the red fluorescence emitted from the cytoplasm of tumor cells using a fluorescence microscope. A “weak fluorescence” indicated a reduction in the tumor cell density, whereas “no fluorescence” did not indicate the complete eradication of the tumor cells, but indicated that few tumor cells were emitting fluorescence. Conclusion: The rapid intraoperative detection of fluorescence from glioma cells using a compact fluorescence microscope was probably useful to evaluate the presence of tumor cells in the resection cavity walls, and could provide surgical implications for the more complete resection of malignant gliomas.

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

1986 ◽  
Vol 65 (4) ◽  
pp. 495-502 ◽  
Author(s):  
Hideyuki Saya ◽  
Takashi Masuko ◽  
Takashi Kokunai ◽  
Hideo Yagita ◽  
Akihiro Ijichi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cultured Cells ◽  
Periodic Acid ◽  
Glioma Cells ◽  
Immunoperoxidase Staining ◽  
Low Grade ◽  
Human Tissues ◽  
Human Glioma ◽  
Content Type ◽  
Rat Glioma

✓ 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.

Interstitial laser photochemotherapy of rhodamine-123-sensitized rat glioma

1987 ◽  
Vol 67 (6) ◽  
pp. 889-894 ◽  
Author(s):  
Stephen K. Powers ◽  
William C. Beckman ◽  
J. Tony Brown ◽  
Linda C. Kolpack
Keyword(s):  
Laser Light ◽  
Malignant Gliomas ◽  
Argon Laser ◽  
Rhodamine 123 ◽  
Adult Rats ◽  
Content Type ◽  
Rat Glioma ◽  
Original Tumor ◽  
Interstitial Laser

✓ The effect of interstitial laser photochemotherapy with the mitochondrial-specific intravital dye rhodamine-123 (Rh-123) was studied using a malignant rat glioma model system (RT2). Tumors were transplanted subcutaneously into the flank of athymic mice and into the cerebrum of adult rats. The Rh-123 photosensitization was produced by direct intratumoral injection of Rh-123 into the mouse RT2 flank tumors and by intravenous Rh-123 administration to adult rats with implanted RT2 intracerebral tumors. Intratumoral irradiation with 150 mW of argon laser light for an exposure time of 15 minutes was performed using a conical sapphire-tipped quartz optical fiber. Control groups of animals received either no treatment, Rh-123 injections, or administration of 150 mW of argon laser light for 15 minutes. Both flank and intracerebral tumors showed progressive diminution in size after treatment with Rh-123 photochemotherapy. There was no evidence of tumor recurrence in 60% of Rh-123 photochemotherapy-treated tumors. Recurrences in tumors treated with Rh-123 photochemotherapy usually appeared at the periphery of the original tumor at 10 days after treatment. Histologically, photochemotherapy-treated intracerebral tumors showed progressive shrinkage with increasing tumor necrosis over time. The finding of residual or recurrent tumor at the periphery of the original tumor mass suggests that the lack of penetration of the blue-green (argon) light was responsible for preventing complete tumor ablation. Our results suggest that Rh-123 photochemotherapy can destroy malignant gliomas in vivo; however, the poor penetrability of the photoactivating blue-green light may limit the effectiveness of this treatment for large or extensively invasive tumors.

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