Response of cultured human glioblastomas to radiation and BCNU chemotherapy

1974 ◽  
Vol 41 (3) ◽  
pp. 339-349 ◽  
Author(s):  
John Mealey ◽  
Tsu T. Chen ◽  
Robert Shupe
Keyword(s):  
Ionizing Radiation ◽  
Tumor Cells ◽  
Mammalian Cells ◽  
Radiation Treatment ◽  
Malignant Gliomas ◽  
Cell Loss ◽  
Response To Treatment ◽  
Glial Tumor ◽  
Content Type ◽  
Effects Of Radiation

✓Individual and combined effects of ionizing radiation and chemotherapy with 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) on glial tumor cells were assessed in cultures derived from human glioblastomas. Drug and radiation exposures were performed on cell monolayers in 0.02 ml wells of microtest plates. Response to treatment was determined from serial observations on surviving populations in the original wells and comparisons with matched control cultures. Chemosensitivity was more variable than radiosensitivity in cell lines derived from five different glioblastomas: BCNU caused growth inhibition of 4% to 85% in doses of 8 µg/ml for 3 days compared to a 40% to 73% reduction after 400 rads of radiation. These findings were all significant statistically. Single doses above 600 to 800 rads appeared lethal, causing widespread loss of cells or transformation into giant forms that did not multiply. The doseresponse curves after BCNU and radiation treatment of cultured glial tumor cells were exponential, demonstrating that both modalities affected a constant fraction of the exposed cell populations according to dose. The observations on radiosensitivity of human glial tumor cells conformed to the generally known responses of cultured normal and neoplastic mammalian cells to ionizing radiation. BCNU in the higher doses tested acted as a possible radiosensitizing agent to potentiate the lethal effects of radiation since an increased rate of cell loss was demonstrated in glioma cultures exposed to this drug and radiation compared to those treated only by irradiation. These results in a controlled experimental environment support the concept that a combination of BCNU and radiation therapy should increase the time of survival of patients with malignant gliomas.

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.

Radiation-induced intracranial malignant gliomas

1989 ◽  
Vol 71 (1) ◽  
pp. 77-82 ◽  
Author(s):  
Scott Shapiro ◽  
John Mealey ◽  
Carl Sartorius
Keyword(s):  
Central Nervous System ◽  
Radiation Necrosis ◽  
External Beam Radiotherapy ◽  
Malignant Gliomas ◽  
Interstitial Brachytherapy ◽  
External Beam ◽  
Glial Tumor ◽  
Content Type ◽  
Radiation Induced ◽  
Fine Print

✓ The authors present seven cases of malignant gliomas that occurred after radiation therapy administered for diseases different from the subsequent glial tumor. Included among these seven are three patients who were treated with interstitial brachytherapy. Previously reported cases of radiation-induced glioma are reviewed and analyzed for common characteristics. Children receiving central nervous system irradiation appear particularly susceptible to induction of malignant gliomas by radiation. Interstitial brachytherapy may be used successfully instead of external beam radiotherapy in previously irradiated, tumor-free brain, and thus may reduce the risk of radiation necrosis.

scholarly journals Extraneural Metastasis of Primary Glioma Occurring in a Setting of Occupational Ionizing Radiation Exposure

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Nitya Prabhakaran ◽  
Douglas C. Miller ◽  
N. Scott Litofsky ◽  
Shellaine R. Frazier
Keyword(s):  
Ionizing Radiation ◽  
Brain Tumors ◽  
Radiation Exposure ◽  
Malignant Gliomas ◽  
Glial Tumor ◽  
Primary Brain Tumors ◽  
Nuclear Disaster ◽  
Dismal Prognosis ◽  
Physical Barriers ◽  
Ionizing Radiation Exposure

Malignant gliomas account for 60% of all primary brain tumors in adults. Glioblastoma Multiforme (GBM) is the most common primary glial tumor with a dismal prognosis and a median survival of approximately 14 months. Extra-neural metastases from primary brain tumors are unusual with an incidence rate of less than 2%. This has been attributed to factors such as short survival, lack of true lymphatics in the CNS, and physical barriers provided by the dura, extracellular matrix, and basement membrane. Although most GBMs occur sporadically, there is a known association with therapeutic radiation exposure and with work in nuclear disaster cleanup. To our knowledge, no case of GBM with metastasis occurring in a patient with occupational radiation exposure currently exists in the literature. In this article, we present a case of GBM with lung metastasis occurring in a 51-year-old Caucasian male, whose history is significant for occupational exposure to ionizing radiation, and review the literature on GBM risk factors and potential mechanisms of metastasis.

scholarly journals Analysis of Factors Affecting 5-ALA Fluorescence Intensity in Visualizing Glial Tumor Cells—Literature Review

2022 ◽  
Vol 23 (2) ◽  
pp. 926
Author(s):  
Marek Mazurek ◽  
Dariusz Szczepanek ◽  
Anna Orzyłowska ◽  
Radosław Rola
Keyword(s):  
Tumor Cells ◽  
Fluorescent Dyes ◽  
Light Emission ◽  
Aminolevulinic Acid ◽  
Accurate Determination ◽  
Malignant Gliomas ◽  
Tumor Resection ◽  
Genetic Profile ◽  
Glial Tumor ◽  
Factors Affecting

Glial tumors are one of the most common lesions of the central nervous system. Despite the implementation of appropriate treatment, the prognosis is not successful. As shown in the literature, maximal tumor resection is a key element in improving therapeutic outcome. One of the methods to achieve it is the use of fluorescent intraoperative navigation with 5-aminolevulinic acid. Unfortunately, often the level of fluorescence emitted is not satisfactory, resulting in difficulties in the course of surgery. This article summarizes currently available knowledge regarding differences in the level of emitted fluorescence. It may depend on both the histological type and the genetic profile of the tumor, which is reflected in the activity and expression of enzymes involved in the intracellular metabolism of fluorescent dyes, such as PBGD, FECH, UROS, and ALAS. The transport of 5-aminolevulinic acid and its metabolites across the blood–brain barrier and cell membranes mediated by transporters, such as ABCB6 and ABCG2, is also important. Accompanying therapies, such as antiepileptic drugs or steroids, also have an impact on light emission by tumor cells. Accurate determination of the factors influencing the fluorescence of 5-aminolevulinic acid-treated cells may contribute to the improvement of fluorescence navigation in patients with highly malignant gliomas.

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.

Late appearance of meningioma at the site of partially removed oligodendroglioma

1975 ◽  
Vol 43 (1) ◽  
pp. 80-85 ◽  
Author(s):  
Junichi Tanaka ◽  
Julio H. Garcia ◽  
Martin G. Netsky ◽  
J. Powell Williams
Keyword(s):  
Ionizing Radiation ◽  
Surgical Trauma ◽  
Glial Tumor ◽  
Content Type ◽  
Fine Print

✓ A case is presented in which a meningioma and a glioma grew in the region where, 23 years before, a glial tumor had been partially removed and irradiated. The authors suggest that surgical trauma and ionizing radiation may have influenced the tumor's development.

Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis

1995 ◽  
Vol 83 (2) ◽  
pp. 285-290 ◽  
Author(s):  
Tom Mikkelsen ◽  
Pei-Sha Yan ◽  
Khang-Loon Ho ◽  
Mansoureh Sameni ◽  
Bonnie F. Sloane ◽  
...  
Keyword(s):  
Cathepsin B ◽  
Tumor Invasion ◽  
Malignant Gliomas ◽  
Neuronal Cell ◽  
Immunohistochemical Analysis ◽  
Normal Brain ◽  
Glial Tumor ◽  
Content Type ◽  
Neuronal Cell Bodies ◽  
Fine Print

✓ The poor prognosis of patients with malignant gliomas is at least partially due to the invasive nature of these tumors. In this study, the authors investigated the possibility that the cysteine protease cathepsin B (CB) is a participant in the process of glial tumor cell invasion. To accomplish this, an immunohistochemical analysis was made of the localization of antibodies to CB in biopsies of five specimens of normal brain, 16 astrocytomas, 33 anaplastic astrocytomas, and 33 glioblastomas multiforme. Staining was scored according to the percentage of positive cells and the intensity of the stain, graded from 0 to 3+. Staining for CB was not seen in any of five samples of normal brain except for occasional neuronal cell bodies and microglia. Only five (31%) of 16 astrocytomas showed a small percentage of positive cells (0.01%–3%) that were stained in a light, diffuse cytoplasmic pattern (1+). Twenty-nine (87.8%) of 33 anaplastic astrocytomas showed positive light, granular staining in 2% to 40% of cells. In anaplastic astrocytoma, the staining within a tumor was heterogeneous with intensities of 1+ (17%), 1+ to 2+ (29%), or 2+ (55%). In contrast, all 33 (100%) glioblastomas were positive in 10% to 90% of cells. The staining was present in a coarse, granular pattern with an intensity of 2+ (12%) or 3+ (88%). Tumor cells infiltrating into brain adjacent to malignant gliomas stained positively in 26 cases that could be evaluated for glioblastoma multiforme; these invading cells frequently followed penetrating blood vessels as typical “secondary structures of Scherer.” Moderate to intense CB staining associated with endothelial proliferation in high-grade tumors was also observed, especially in regions of tumor infiltration into adjacent normal brain. These results provide evidence consistent with the hypothesis that CB is functionally significant in the process of tumor invasion and angiogenesis in the clinical progression of the malignant phenotype in astrocytomas.

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.

Improved treatment of a brain-tumor model

1983 ◽  
Vol 58 (3) ◽  
pp. 368-373 ◽  
Author(s):  
Massimo A. Gerosa ◽  
Dolores V. Dougherty ◽  
Charles B. Wilson ◽  
Mark L. Rosenblum
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Total Dose ◽  
Tumor Cells ◽  
Malignant Gliomas ◽  
Tumor Model ◽  
Content Type ◽  
Cell Kill ◽  
Brain Tumor Model ◽  
Anti Tumor Activity

✓ A combination chemotherapy regimen for brain tumors was developed, based on investigations of the survival of animals harboring the intracerebral 9L rat brain-tumor model and on analyses of their clonogenic tumor cells. Fischer 344 rats harboring 9L brain tumors were treated with 2-day courses of 5-fluorouracil (5-FU), in order to expose all cycling tumor cells to the drug during DNA synthesis and achieve maximum anti-tumor activity for this cell-cycle-specific anti-metabolite. Although a 74% cell kill was obtained for a total dose of 45 mg/kg or greater, animal life span was not increased over that of untreated tumor-bearing controls. However, when 5-FU (48 to 96 mg/kg total dose over 2 days) was administered after a single LD10 dose of BCNU (13.3 mg/kg), additive cell kill was suggested. In three large series, long-term animal survivors and occasional tumor cures were observed with this drug combination, a result never observed following BCNU alone. Schedule dependency was not apparent. A previously published protocol for treating recurrent malignant gliomas with sequential courses of BCNU and 5-FU was partially planned based upon these initial observations. Anti-tumor activity with the combination of drugs was superior to therapy with BCNU alone. Both animal and human studies confirm that, contrary to presently accepted oncological tenets, a chemotherapeutic agent that kills significant numbers of tumor cells but is clinically ineffective when given alone might, nevertheless, be useful in combination therapy regimens.

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