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.

The deposition of Hg203-chlormerodrin in experimental brain tumors

1971 ◽  
Vol 35 (3) ◽  
pp. 303-308 ◽  
Author(s):  
Tatsuya Kobayashi ◽  
Louis Bakay ◽  
Joseph C. Lee
Keyword(s):  
Brain Tumors ◽  
Tumor Cells ◽  
Normal Brain ◽  
Intracranial Tumors ◽  
Electron Microscopic ◽  
Electron Microscopic Autoradiography ◽  
Content Type ◽  
Meningeal Tumors ◽  
Vacuolar System ◽  
Fine Print

✓ The deposition of Hg203-chlormerodrin was studied in intracranial tumors in mice induced by implantation of 20-methyl cholanthrene by tissue assay, as well as light microscopic and electron microscopic autoradiography. The investigations were carried out in astrocytomas, glioblastomas, and meningeal tumors. The chlormerodrin content of the tumors exceeded that of normal brain with a significant tumor/brain ratio ranging from 5.8 to 22.5. It was found that the chlormerodrin molecule becomes rapidly incorporated in the tumor cells, with a preference for that portion of the cytoplasm associated with the vacuolar system.

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.

Dexamethasone-induced abolition of the inflammatory response in an experimental glioma model: a flow cytometry study

2000 ◽  
Vol 93 (4) ◽  
pp. 634-639 ◽  
Author(s):  
Behnam Badie ◽  
Jill M. Schartner ◽  
Jasmeet Paul ◽  
Becky A. Bartley ◽  
Jessica Vorpahl ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Brain Tumors ◽  
Ex Vivo ◽  
Cell Infiltration ◽  
Cytotoxic T Cell ◽  
Content Type ◽  
Rat Glioma ◽  
Infiltrating Cells ◽  
Glioma Model ◽  
Fine Print

Object. Commonly used for management of cerebral edema in patients with brain tumors, steroid medications also have immunosuppressive functions. To characterize the effects of steroids on the central nervous system's response to tumors more clearly, flow cytometry was used to quantify the extent of inflammatory cell infiltration in an immunogenic rat glioma model.Methods. Freshly prepared 11-day-old intracranial C6 tumors that had been excised from dexamethasone-treated and untreated rats were labeled ex vivo with monoclonal antibodies against CD11b/c, CD45, and CD8a antigens. The extent of microglia (CD11b/c—highly positive, CD45—slightly positive cell), macrophage (CD11b/c—highly positive, CD45—highly positive cell), lymphocyte (CD11b/c-negative, CD45—highly positive cell), and cytotoxic T-cell (CD8a-positive cell) infiltration into each rat's tumor, tumor periphery, and contralateral tumor-free hemisphere was analyzed using flow cytometry.Microglia and lymphocytes constituted a significant component of infiltrating cells in this model, comprising 23 ± 3% and 33 ± 5% of viable cells, respectively. Macrophages, on the other hand, accounted for only 9 ± 1% of infiltrating cells. Treatment of rats with a 7-day course of low-dose dexamethasone (0.1 mg/kg/day) resulted in a greater than 50% inhibition of microglia (p = 0.03) and lymphocyte (p = 0.001) infiltration into tumors. Increasing the dexamethasone dose to 1 mg/kg/day further abolished lymphocyte infiltration (89% inhibition, p = 0.001) but had no additional inhibitory effect on microglia invasion. Macrophage infiltration of tumors was not inhibited at the dexamethasone doses used in this study (p = 0.42).Conclusions. Flow cytometry is a valuable technique for characterizing tumor-associated inflammatory cells in gliomas. Even at low doses, dexamethasone was found to inhibit significantly the infiltration of brain tumors by lymphocytes and microglia. These findings should be considered when experimental immunotherapeutic strategies are evaluated for clinical application.

Uptake of tritiated methotrexate by mouse brain tumors after intravenous or intrathecal administration

1974 ◽  
Vol 40 (6) ◽  
pp. 706-716 ◽  
Author(s):  
Yukitaka Ushio ◽  
Toru Hayakawa ◽  
Heitaro Mogami
Keyword(s):  
Brain Tumors ◽  
Brain Tissue ◽  
Intravenous Injection ◽  
Malignant Gliomas ◽  
Intrathecal Administration ◽  
Drug Dosage ◽  
Content Type ◽  
Radioactive Assay ◽  
The Brain ◽  
Fine Print

✓ Malignant gliomas were induced in strain ddN mice by intracerebral implantation of a 20-methylcholanthrene pellet. The uptake and distribution of tritiated methotrexate (MTX-3H) in the tumor were investigated by radioactive assay and radioautography after single intravenous or intrathecal injections. By either route, a large amount of MTX-3H was taken up by gliomas, and a significantly higher concentration was observed in tumor than in the brain tissue. At 24 hours after intrathecal administration, the uptake of MTX-3H by gliomas exceeded that achieved after intravenous injection, although the drug dosage in the latter was 10 times that in the former.

Potent and specific killing of human malignant brain tumor cells by an anti-transferrin receptor antibody-ricin immunotoxin

1987 ◽  
Vol 66 (6) ◽  
pp. 850-861 ◽  
Author(s):  
John Zovickian ◽  
Virginia Gray Johnson ◽  
Richard J. Youle
Keyword(s):  
Tumor Cells ◽  
Transferrin Receptor ◽  
Solid Phase ◽  
Target Cells ◽  
Neoplastic Disease ◽  
Normal Brain ◽  
Plant Toxin ◽  
Content Type ◽  
Hybrid Molecules ◽  
Fine Print

✓ Immunotoxins are hybrid molecules which combine the exquisite selectivity of monoclonal antibodies with the potent toxicity of protein toxins. An immunotoxin was constructed by linking a murine monoclonal antibody against the human transferrin receptor (TR) to the plant toxin, ricin. The cytotoxic activity of the anti-TR-ricin immunotoxin was tested in vitro and demonstrated highly potent and cell type-specific killing of cells derived from human glioblastoma, medulloblastoma, and leukemia. The anti-TR-ricin immunotoxin killed more than 50% of “target” cells at a concentration of 5.6 × 10−13 M after an 18-hour incubation with the ionophore, monensin. This potency exceeds that of any other anti-TR immunotoxin reported in the literature. When the activity of the anti-TR-ricin immunotoxin against “target” tumor-derived cells was compared with the immunotoxin's activity against “non-target” cells, it could be predicted that a selective toxicity of anti-TR-ricin immunotoxin between tumor cells and normal brain was more than 150- to 1380-fold. Solid-phase indirect radioimmunoassay techniques were used to demonstrate significantly higher levels of TR in the glioblastoma- and medulloblastoma-derived cell lines, as well as in surgical tissue samples of medulloblastoma and glioblastoma, as compared to normal brain. Immunotoxins targeted to the TR may possess sufficient specificity to be of therapeutic importance, particularly to treat neoplastic disease of the central nervous system involving compartments (such as intrathecal, intraventricular, or cystic) where delivery of immunotoxins to tumor would not require transvascular transport.

Dynamic determination of human glioma invasion in vitro

1998 ◽  
Vol 89 (3) ◽  
pp. 441-447 ◽  
Author(s):  
Svein J. T. Nygaard ◽  
Hans K. R. Haugland ◽  
Ole Didrik Laerum ◽  
Morten Lund-Johansen ◽  
Rolf Bjerkvig ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Brain Tissue ◽  
Normal Brain ◽  
Tumor Spheroids ◽  
Normal Brain Tissue ◽  
Content Type ◽  
Biopsy Specimens ◽  
Fine Print

Object. The goal of this study was to evaluate whether there is any relationship between survival of patients with brain tumor and tumor proliferation or tumor invasion in vitro. Methods. Samples of freshly resected brain tumors from 14 patients with glioblastoma multiforme (GBM) were directly grown as three-dimensional multicellular spheroids. The tumor spheroids were cocultured with fetal rat brain cell aggregates (BCAs), used to represent an organotypical normal brain tissue model. Before the coculture, the tumor spheroids and the BCAs were stained with two different carbocyanine dyes, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) and 3,3′-dioctadecycloxacarbocyanine perchlorate (DiO), respectively. During the coculture, confocal laser scanning microscopy allowed a sequential analysis of tumor cell invasion by visualizing dynamic aspects of the invasive process. Single cocultures were examined at three different time points (24, 48, and 96 hours). During the observation period there was a change in the structural morphology of the cocultures, with a progressive decrease in BCA volume. Furthermore, the scanning confocal micrographs revealed a bidirectional movement of tumor cells and normal cells into brain and tumor tissue, respectively. It is also shown that there is a considerable variation in the rate of BCA destruction in cocultures of glioma spheroids generated directly from biopsy specimens. This variation is seen both between spheroids generated from the same biopsy as well as between spheroids that are grown from different biopsy specimens. Cell proliferation measured by Ki-67 immunohistochemical analysis of biopsy samples obtained in the same patients revealed a correlation between tumor cell proliferation and tissue destruction of the BCAs, as determined by a reduction in BCA volume (p = 0.0338). No correlation was found when survival was related to the same parameters (p > 0.05). Conclusions. The present work provides a model for quick and efficient assessment of dynamic interactions between tumor and normal brain tissue shortly after surgery.

The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers

1992 ◽  
Vol 76 (4) ◽  
pp. 640-647 ◽  
Author(s):  
Stuart A. Grossman ◽  
Carla Reinhard ◽  
O. Michael Colvin ◽  
Mark Chasin ◽  
Robert Brundrett ◽  
...  
Keyword(s):  
New Zealand ◽  
Brain Tissue ◽  
Direct Injection ◽  
Normal Brain ◽  
Local Concentration ◽  
Content Type ◽  
Drug Concentrations ◽  
New Zealand White Rabbits ◽  
The Brain ◽  
Fine Print

✓ The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time. The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 µg BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.

The effect of craniectomy on the biomechanics of normal brain

1987 ◽  
Vol 67 (4) ◽  
pp. 573-578 ◽  
Author(s):  
Shizuo Hatashita ◽  
Julian T. Hoff
Keyword(s):  
White Matter ◽  
Brain Tissue ◽  
Volume Index ◽  
Normal Brain ◽  
Tissue Pressure ◽  
Content Type ◽  
Cerebrovascular Resistance ◽  
Tissue Resistance ◽  
Tissue Compliance ◽  
Fine Print

✓ Does an open skull alter the fundamental biomechanical properties of normal brain tissue? This question was studied in 32 anesthetized cats, 16 of which underwent a standard craniectomy (2.5 × 2.0 cm) in the left frontoparietal region. Brain tissue pressure, regional cerebral blood flow (rCBF), and brain water content were measured from the same area of cortical gray and white matter, and intracranial pressure (ICP) was recorded from the cisterna magna. Brain tissue resistance, tissue compliance, and the pressure-volume index were analyzed in response to a bolus injection of saline into brain tissue or the cisterna magna. Cerebrovascular resistance was also calculated. In craniectomized animals 2 hours after surgery, ICP had fallen to 3.75 ± 0.39 mm Hg, and cortical gray and white matter tissue pressure had fallen to 3.19 ± 0.47 and 4.69 ± 0.54 mm Hg, respectively (mean ± standard error of the mean); these variables did not fall further over 4 hours. The pressure-volume index in the same animals increased significantly from 0.67 ± 0.01 to 0.86 ± 0.04 ml. Tissue compliance rose in the cortical gray matter but tissue resistance fell, approximating that found in subjacent white matter. There was no significant difference between animals with and without craniectomy in rCBF, cerebrovascular resistance, or brain water content in either gray or white matter. These findings indicate that in the cat craniectomy causes an increase in the compensatory capacity of the intracranial cavity to increased volume. The data also indicate that cortical tissue has high hydraulic conductivity and compliance when the skull is opened.

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.

Quantitative study of microvessel ultrastructure in human peritumoral brain tissue

1987 ◽  
Vol 67 (5) ◽  
pp. 697-705 ◽  
Author(s):  
Patricia A. Stewart ◽  
Kay Hayakawa ◽  
Catherine L. Farrell ◽  
Rolando F. Del Maestro
Keyword(s):  
Blood Vessels ◽  
Tumor Cells ◽  
Brain Tissue ◽  
Structural Characteristics ◽  
Tissue Samples ◽  
Content Type ◽  
Form And Function ◽  
Essentially Normal ◽  
Inducing Factors ◽  
Fine Print

✓ The form and function of blood vessels are determined by the cells that constitute their microenvironment. Brain tissue around tumors contains varying numbers of tumor cells that could influence local capillaries to lose their blood-brain barrier (BBB), as they do in the tumor itself. Microvascular permeability cannot be measured directly in humans but can be inferred from a knowledge of vessel ultrastructure. The authors have examined the vascular ultrastructure associated with the BBB in human peritumoral brain tissue for evidence of BBB compromise and to correlate BBB features with the cellular components of the vessel microenvironment. Light microscopic examination of brain tissue samples in patients with primary brain tumors showed that the tissue lying beyond the visible edge of the tumor ranged from essentially normal to grossly infiltrated with tumor cells. Although some of the vessels were structurally normal, the microvessels as a group had elongated junctional clefts (unfused regions) and an increase in the density of endothelial vesicles. Furthermore, the cleft index (the percentage of the junctional profile that is unfused) varied directly with the local cell density. A subpopulation of vessels enveloped by a layer of tumor cells was grossly abnormal. However, vessels that were not immediately invested by tumor cells also showed some abnormalities. It is concluded that tumor cells infiltrating peritumoral brain tissue cause blood vessels to take on some of the structural characteristics of leaky vessels. Since direct contact is not required, and since the degree of abnormality correlates with the number of tumor cells in the environment, the authors suggest that this inductive influence is exerted over a distance and is dependent on the concentration of the inducing factors.

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