Immunosuppression by phenytoin: implication for altered immune competence in brain-tumor patients

1984 ◽  
Vol 61 (6) ◽  
pp. 1085-1090 ◽  
Author(s):  
Kenji Kikuchi ◽  
Christopher I. McCormick ◽  
Edward A. Neuwelt
Keyword(s):  
Brain Tumor ◽  
Culture Medium ◽  
Thymidine Incorporation ◽  
Pokeweed Mitogen ◽  
Immune Competence ◽  
Lymphocyte Function ◽  
Tumor Patients ◽  
Content Type ◽  
Anticonvulsant Agent

✓ This investigation was conducted to examine the immunosuppressive potential of phenytoin in vivo and to document a correlation between phenytoin therapy and depressed lymphocyte responsiveness to mitogens. It was thought that phenytoin, the most widely used anticonvulsant agent, may play some role in the immunosuppression seen in brain-tumor patients. The effect of phenytoin on mitogen-stimulated lymphocyte function was evaluated by tritiated (3H)-thymidine incorporation and lymphocyte nuclear size distribution. Lymphocytes from either phenytoin-treated or normal rabbits were incubated for 90 hours in culture medium in the presence of three mitogens: phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM). Significant suppression of mitogen-induced activation of the lymphocytes from treated animals was demonstrated. The present studies suggest a possible connection between phenytoin therapy and altered immune competence in brain-tumor patients.

Presence of immunosuppressive factors in brain-tumor cyst fluid

1983 ◽  
Vol 59 (5) ◽  
pp. 790-799 ◽  
Author(s):  
Kenji Kikuchi ◽  
Edward A. Neuwelt
Keyword(s):  
Brain Tumor ◽  
Culture Medium ◽  
Cellular Proliferation ◽  
Lymphocyte Activation ◽  
Cyst Fluid ◽  
Pokeweed Mitogen ◽  
Lymphocyte Function ◽  
Tumor Patients ◽  
Cell Size Distribution

✓ The present investigation was conducted to examine the effects upon normal lymphocyte activation of the addition of brain-tumor cyst fluid or cerebrospinal fluid (CSF) to an in vitro culture system. It was believed that factors present in these fluids may play a role in local and systemic immunosuppression in brain-tumor patients. The authors evaluated the effect of the cyst fluid, CSF, and serum from eight patients with brain tumors (one astrocytoma, five glioblastoma multiforme, one medulloblastoma, and one microglioma) on mitogen-stimulated lymphocyte function as measured by 3H-thymidine incorporation, cell size distribution, and cellular proliferation. Lymphocytes from normal volunteers were incubated for 90 hours in culture medium with 10% pooled human serum, mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen), and a range of volumes of cyst fluid or CSF from the tumor patients. Significant suppression of mitogen-induced activation of the lymphocytes was demonstrated in the presence of cyst fluid from five out of six patients, but the mitogen response was only minimally affected by the addition of the CSF from these patients to the culture medium. The suppression of lymphocyte activation by cyst fluid was directly proportional in several cases to the concentration of the cyst fluid. The total protein, albumin, and immunoglobulin (Ig) concentrations in the cyst fluids were observed to roughly correspond to the serum levels and were much higher than in CSF. These studies suggest that brain-tumor cells locally produce lymphocyte-suppressive factors which may then be released into blood. Preliminary characterization of the suppressive factor(s) responsible for the inhibition of lymphocyte function indicates that they are non-dialyzable and do not appear to be an IgG.

scholarly journals Immunologic stimulation of early murine hematopoiesis and its abrogation by cyclosporin A

Blood ◽  
1982 ◽  
Vol 59 (4) ◽  
pp. 851-856 ◽  
Author(s):  
SA Burstein ◽  
SK Erb ◽  
JW Adamson ◽  
LA Harker
Keyword(s):  
Immune Response ◽  
Cyclosporin A ◽  
Progenitor Cells ◽  
Pokeweed Mitogen ◽  
Normal Rabbit Serum ◽  
Lymphocyte Function ◽  
Spleen Cells ◽  
Stimulation Of

Abstract Mice injected chronically with antiplatelet serum develop an increase in the number of megakaryocytic progenitor cells compared to animals given normal rabbit serum. To examine the specificity of this response, progenitor cells giving rise to megakaryocyte, granulocyte-macrophage, erythroid, and mixed-cell colonies were assayed after injection of various heterosera or saline. All four colony types increased in the serum-treated groups. Since the in vitro proliferation of hematopoietic progenitor cells is promoted by supernatants of mitogen-stimulated spleen cells, we hypothesized that the immune response following antiserum administration resulted in the in vivo activation of T lymphocytes which produced or led to the production of colony stimulating activities. To test this hypothesis, cyclosporin A, a preferential inhibitor of T lymphocyte function, was given to mice concurrently with antiserum and also added to spleen cell cultures in the presence of pokeweed mitogen. Cyclosporin A abrogated the antiserum- related increases in progenitor cell numbers in vivo and the production of colony stimulating activity in vitro. The results suggest that the immune response related to antiserum administration results in the in vivo production of hematopoietic colony stimulating activities that may be identical to those produced in vitro by mitogen-stimulation of spleen cells.

scholarly journals Immunologic stimulation of early murine hematopoiesis and its abrogation by cyclosporin A

Blood ◽  
1982 ◽  
Vol 59 (4) ◽  
pp. 851-856 ◽  
Author(s):  
SA Burstein ◽  
SK Erb ◽  
JW Adamson ◽  
LA Harker
Keyword(s):  
Immune Response ◽  
Cyclosporin A ◽  
Progenitor Cells ◽  
Pokeweed Mitogen ◽  
Normal Rabbit Serum ◽  
Lymphocyte Function ◽  
Spleen Cells ◽  
Stimulation Of

Mice injected chronically with antiplatelet serum develop an increase in the number of megakaryocytic progenitor cells compared to animals given normal rabbit serum. To examine the specificity of this response, progenitor cells giving rise to megakaryocyte, granulocyte-macrophage, erythroid, and mixed-cell colonies were assayed after injection of various heterosera or saline. All four colony types increased in the serum-treated groups. Since the in vitro proliferation of hematopoietic progenitor cells is promoted by supernatants of mitogen-stimulated spleen cells, we hypothesized that the immune response following antiserum administration resulted in the in vivo activation of T lymphocytes which produced or led to the production of colony stimulating activities. To test this hypothesis, cyclosporin A, a preferential inhibitor of T lymphocyte function, was given to mice concurrently with antiserum and also added to spleen cell cultures in the presence of pokeweed mitogen. Cyclosporin A abrogated the antiserum- related increases in progenitor cell numbers in vivo and the production of colony stimulating activity in vitro. The results suggest that the immune response related to antiserum administration results in the in vivo production of hematopoietic colony stimulating activities that may be identical to those produced in vitro by mitogen-stimulation of spleen cells.

Assessment of brain tumor cell motility in vivo and in vitro

1995 ◽  
Vol 82 (4) ◽  
pp. 615-622 ◽  
Author(s):  
Michael R. Chicoine ◽  
Daniel L. Silbergeld
Keyword(s):  
Brain Tumor ◽  
Cell Motility ◽  
Human Brain Tumor ◽  
Content Type ◽  
Brain Tumor Cells ◽  
Tumor Cell Motility ◽  
Brain Tumor Cell ◽  
Fine Print

✓ Brain tumor dispersal far from bulk tumor contributes to and, in some instances, dominates disease progression. Three methods were used to characterize brain tumor cell motility in vivo and in vitro: 1) 2 weeks after implantation in rat cerebral cortex, single C6 cells labeled with a fluorescent tag had migrated to brain sites greater than 16 mm distant from bulk tumor; 2) time-lapse videomicroscopy of human brain tumor cells revealed motility of 12.5 µm/hr. Ruffling leading edges and pseudopod formation were most elaborate in more malignant cells; 3) an in vitro assay was devised to quantitatively evaluate motility from a region of high cell density to one of lower cell density. Human brain tumor cells were plated in the center of a petri dish, washed, and refed, establishing a 2-cm circular zone of cells in the dish center. Motility was determined by counting cells daily at predetermined distances from the central zone perimeter. Cells were found 1 cm from the perimeter by 24 hours and 3 cm from the perimeter by 4 days. Increasing serum concentration increased motility; however, neither fibronectin nor arrest of cells in the G0 phase by hydroxyurea altered motility. The addition of cytochalasin B to block cytoskeletal assembly prevented cell motility. Motility increased with increased malignancy. Subpopulations of cells were created by clonal amplification of cells that had migrated most rapidly to the dish periphery. Although morphologically indistinguishable when compared to the original cell line from which they were derived, these subpopulations demonstrated significantly increased motility.

Limited efficacy of gene transfer in herpes simplex virus-thymidine kinase/ganciclovir gene therapy for brain tumors

2005 ◽  
Vol 102 (2) ◽  
pp. 328-335 ◽  
Author(s):  
Piotr Hadaczek ◽  
Hanna Mirek ◽  
Mitchel S. Berger ◽  
Krystof Bankiewicz
Keyword(s):  
Gene Therapy ◽  
Brain Tumor ◽  
Gene Transfer ◽  
Thymidine Kinase ◽  
Therapeutic Effects ◽  
Content Type ◽  
Over Time ◽  
Fine Print

Object. Low efficacy of gene transfer, transient gene expression, and toxicity of viral vectors are the major hurdles in successful anticancer gene therapy. The authors conducted in vitro (U87MG cell line) and in vivo (xenograft, tumor-bearing rodent model) studies to address the stability of transduction by using the adenoassociated virus serotype-2 (AAV2)—thymidine kinase (TK) vector over time. Methods. Standard methods for cell growth and a ganciclovir (GCV) cytotoxicity assay were applied. The AAV2-TK was infused into implanted tumors in athymic rats via convection-enhanced delivery (CED). Thymidine kinase expression was evaluated through immunohistochemical analysis, and the distribution volumes of the transduced tumors were calculated. Twenty-four hours following the viral infusions, animals were treated with GCV (50 mg/kg intraperitoneally every day for 10 days; six rats) or phosphate-buffered saline (six rats). A rapid decrease in TK expression over time was observed both in vitro and in vivo. A large volume of the tumor (up to 39%) was transduced with AAV2-TK following CED. Administration of GCV resulted in limited therapeutic effects (survival of 25.8 compared with 21.3 days). Conclusions. Rapid elimination of TK expression from dividing tumor cells and focal transduction of the brain tumor were most likely responsible for the limited bystander effect in this approach. Immediate administration of GCV is crucial to assure maximal efficacy in the elimination of cancer cells. In addition, the complete or diffused transduction of a brain tumor with TK may be required for its total eradication.

Effect of tri-iodothyronine on normal human lymphocyte function

1984 ◽  
Vol 101 (1) ◽  
pp. 81-86 ◽  
Author(s):  
A. P. Weetman ◽  
A. M. McGregor ◽  
M. Ludgate ◽  
R. Hall
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Cell Function ◽  
Human Lymphocytes ◽  
T Cell Subsets ◽  
Pokeweed Mitogen ◽  
Lymphocyte Function ◽  
Normal Human

ABSTRACT The effect of excessive tri-iodothyronine (T3) in vivo was assessed using normal human lymphocytes. Cells from normal subjects were frozen in liquid nitrogen before and after oral administration of T3 for 1 week to permit a direct comparison under identical culture conditions. Within the group of individuals studied, some subjects did show changes in B or T cell function but hypertri-iodothyroninaemia produced no consistent effect for the whole group on circulating T cell subsets or T and B cell activation measured by short-term culture or stimulation of lymphocyte cultures with phytohaemagglutinin or pokeweed mitogen. Tri-iodothyronine supplementation of cultures in vitro did not affect pokeweed mitogen stimulation. These findings suggest that the immunological abnormalities in Graves' disease are not the result of increased circulating thyroid hormone levels and that remission following medical treatment is due to an immuno-suppressive effect of the drug rather than the restoration of euthyroidism. J. Endocr. (1984) 101,81–86

Decreased cerebral glucose metabolism in patients with brain tumors: an effect of corticosteroids

1995 ◽  
Vol 83 (4) ◽  
pp. 657-664 ◽  
Author(s):  
Michael J. Fulham ◽  
Arturo Brunetti ◽  
Luigi Aloj ◽  
Ramesh Raman ◽  
Andrew J. Dwyer ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Glucose Metabolism ◽  
Brain Tumors ◽  
Fdg Pet ◽  
Cerebral Glucose Metabolism ◽  
Tumor Patients ◽  
Subsequent Increase ◽  
Content Type ◽  
Normal Volunteers ◽  
Pet Scans

✓ The authors measured cerebral glucose metabolism (CMRglu) using [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in patients with brain tumors to evaluate the effect of exogenous corticosteroids (in this instance, dexamethasone) on glucose metabolism. Fifty-six FDG-PET studies obtained in 45 patients with unilateral supratentorial brain tumors were analyzed. Patients with brain tumors were divided into three groups: 1) patients with cushingoid symptoms, who had been treated with combinations of radiotherapy and chemotherapy taking oral dexamethasone; 2) patients not taking dexamethasone but treated with radiotherapy; and 3) patients not taking dexamethasone who had not been treated with radiotherapy. Serial FDG-PET scans were obtained in eight of the cushingoid patients. Glucose metabolism was measured in the contralateral cerebral and ipsilateral cerebellar hemispheres in patients and compared to measurements taken from 19 normal volunteers. The authors found that in the cushingoid brain tumor patients there was a marked reduction in CMRglu compared to normal volunteers and other brain tumor patients (Kruskal—Wallis test; p 0.001). In the majority of patients who had serial FDG-PET scans, there was a decline in glucose metabolism over time and in one patient, in whom dexamethasone was reduced in dosage, there was a subsequent increase in CMRglu. The authors conclude that there is a generalized reduction in CMRglu in brain tumor patients taking dexamethasone compared to other brain tumor patients and normal volunteers, and that this effect is independent of radiotherapy, concurrent anticonvulsant medication, and transhemispheric functional disconnection (transhemispheric diaschisis).

In vitro killing of human glioblastoma by interleukin-2-activated autologous lymphocytes

1986 ◽  
Vol 64 (1) ◽  
pp. 114-117 ◽  
Author(s):  
Steven K. Jacobs ◽  
Debra J. Wilson ◽  
Paul L. Kornblith ◽  
Elizabeth A. Grimm
Keyword(s):  
Tissue Culture ◽  
Brain Tumor ◽  
Tumor Cells ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Peripheral Blood Lymphocytes ◽  
Tumor Patients ◽  
Content Type ◽  
Brain Tumor Cells ◽  
Fine Print

✓ Culture of peripheral blood lymphocytes (PBL) from brain-tumor patients with recombinant interleukin-2 (IL-2) results in the activation of lymphokine-activated killer cells (LAK) with the capacity to lyse autologous and allogeneic glioblastoma. In this study, PBL obtained from brain-tumor patients were cultured with or without IL-2 for 3 to 7 days and then tested for their ability to lyse target cells in a 4-hour chromium release cytotoxicity assay. The PBL were drawn 1 to 2 weeks following operative tumor debulking. Cells used as targets included fresh brain-tumor cells obtained at the time of craniotomy, fresh brain-tumor cells grown from 1 to 3 weeks in tissue culture, fresh autologous PBL, and allogeneic glioblastoma cells grown in tissue culture. Peripheral blood lymphocytes from brain-tumor patients that were cultured without IL-2 did not significantly lyse autologous or allogeneic glioblastoma. However, when these PBL were cultured with IL-2, LAK were generated which produced marked lysis of autologous as well as allogeneic tissue-culture glioblastoma in all of eight cases. Significant lysis of autologous fresh tumor by patient LAK was observed in four of five experiments. By contrast, patient LAK did not kill autologous normal PBL. The ability to generate LAK was not influenced by the patient's age, previous therapy, or the administration of steroids.

In vivo incorporation of [9,10-3H]-palmitate into a rat metastatic brain-tumor model

1991 ◽  
Vol 74 (4) ◽  
pp. 643-649 ◽  
Author(s):  
Tadashi Nariai ◽  
Joseph J. DeGeorge ◽  
Nigel H. Greig ◽  
Stanley I. Rapoport
Keyword(s):  
Brain Tumor ◽  
Tumor Cell ◽  
Histological Study ◽  
Brain Slices ◽  
Tumor Model ◽  
Normal Brain ◽  
Intracerebral Injection ◽  
Content Type ◽  
Contralateral Normal Brain

✓ Lipid metabolism of an intracerebrally implanted brain tumor and normal brain was investigated in awake Fischer 344 rats using intravenously injected [9, 10-3H]-palmitate as a probe. A suspension of Walker 256 carcinosarcoma cells (250 cells in 5 µl medium), with or without 1 % low-melting-point agar, was implanted into the caudate nucleus of rats 8 to 9 weeks old. Control animals received an intracerebral injection without tumor cells. Seven days after implantation, awake rats were infused intravenously for 5 minutes with [9, 10-3H]-palmitate (6.4 mCi/kg). The rats were killed 20 minutes after initiation of the infusion and coronal brain slices were obtained for quantitative autoradiography and light histological study. Tumor cell masses were histologically well demarcated from the surrounding brain tissue. Tumor tissue incorporation of [9, 10-3H]- palmitate was heterogeneous, ranging on average from 3.1- to 6.1-fold greater than in the corresponding contralateral brain. In addition, incorporation corresponded to regional tumor cell density. The incorporation rate constant of [9, 10-3H]-palmitate in tumor was significantly increased compared to control brain and was independent of tumor size. Necrotic areas within tumors showed no incorporation of radiolabeled palmitate. Brain surrounding the tumors and control injection sites showed reactive gliosis, and possessed 30% greater incorporation of [9, 10-3H]-palmitate than contralateral normal brain. These results suggest that [9, 10-3H]- palmitate can be used to image brain tumors in vivo, measuring turnover and/or synthesis of tumor and brain lipid.

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