Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vivo, water diffusion displays directionality due to presence of complex microstructural barriers in tissue. The extent of directionality of water diffusion can be expressed as a fractional anisotropy (FA) value, using diffusion tensor MR imaging (DTI). The aim of this study was to determine whether FA values indicate microstructures in astrocytic tumors. We performed DTI in 31 patients with astrocytic tumor, and measured the FA values of tumor and normal brain regions prior to CT-guided stereotactic biopsy. After biopsy, FA values were compared to assess the cellularity and vascularity of tumor tissue. Although mean FA values trended to differ among histological types, all mean tumor FA values were lower than those of normal brain regions. Positive correlation was observed between FA values and both cellularity (r = 0.65, p < 0.05) and vascularity (r = 0.45, p < 0.05). We had hypothesized that the FA value of an astrocytic tumor would be determined by a balance between factors increasing the directionality of water diffusion, such as high cellularity and/or vascularity, and factors decreasing the directionality of water diffusion, such as fiber destruction. However, our results suggest that the FA values of glioblastoma, anaplastic astrocytoma, diffuse astrocytoma and pilocytic astrocytoma are largely affected by cellularity and/or vascularity, whereas that of gliomatosis cerebri are largely affected by the preservation of nerve fibers. Measurement of FA value using DTI will allow prediction of histological characteristics such as cellularity, vascularity and/or fiber structure in astrocytic tumors.
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PMID:Measurement of fractional anisotropy using diffusion tensor MRI in supratentorial astrocytic tumors. 1282 15

Vasogenic edema is one of the most serious clinical problems in brain tumors and tightly connected to water shifts between the different fluid compartments in the brain. Aquaporin water channels have been recognized to have an important impact on the development of edematous swelling in the brain. Astrocytes, which are believed to induce or at least maintain the blood-brain barrier in the brain capillary endothelial cells, express the aquaporin isoform AQP4. Normally, AQP4 is highly concentrated in the glial membrane where astrocytes contact mesenchymal space, such as perivascular or brain superficial regions. Parenchymal membranes do not show any immunocytochemical AQP4-specific signal. We investigated the AQP4 expression in human glioblastoma and correlated it with the expression pattern of the extracellular heparan sulfate proteoglycan agrin and members of the dystrophin-dystroglycan complex. We found that AQP4 completely covered the surface of the glioma cells. alpha-Dystroglycan was absent from glial membranes but retained in endothelial membranes. Utrophin and dystrophin remained restricted to the endfoot membrane in those cells in which AQP4 had been redistributed, whereas alpha-syntrophin redistributed together with AQP4 across the entire cell surface. Since alpha-dystroglycan operates as a binding protein for agrin, these observations support the suggestions that (1) AQP4 is tightly associated with the dystrophin-dystroglycan complex, and (2) agrin is necessary for the polarized distribution of AQP4 in the astrocyte. The results are discussed in connection with the fact that normally AQP4 is assembled in the so-called orthogonal arrays of particles (OAPs). The restriction of AQP4/OAPs to the endfoot membrane may be dependent on the presence of agrin, and this might be essentially connected to the ability of astrocytes to maintain the integrity of the blood-brain barrier.
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PMID:Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. 1473 5

High-resolution magic angle spinning (HR-MAS) one- and two-dimensional 1H and 13C nuclear magnetic resonance (NMR) spectroscopy has been used to study intact glioblastoma (GBM) brain tumour tissue. The results were compared with in vitro chemical extract and in vivo spectra. The resolution of 1H one-dimensional, 1H TOCSY and 13C HSQC HR-MAS spectra is comparable to that obtained on perchloric extracts. 13C HSQC HR-MAS spectra have been particularly useful for the identification of 37 different metabolites in intact biopsy tumours, excluding water and DSS components. To our knowledge, this is the most detailed assignment of biochemical compounds obtained in intact human tissue, in particular in brain tumour tissue. Tissue degradation during the recording of the NMR experiment was avoided by keeping the sample at a temperature of 4 degrees C. Detailed metabolical compositions of 10 GBM (six primary, two secondary and two unclassified) were obtained. A good correlation between ex vivo and in vivo MRS has been found.
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PMID:1H and 13C HR-MAS spectroscopy of intact biopsy samples ex vivo and in vivo 1H MRS study of human high grade gliomas. 1522 32

The total synthesis of 5,10,15,20-tetra[3,5-(carboranylmethyl)phenyl]porphyrins 2-5 containing 36-43% boron by weight are reported. All compounds were characterized by spectroscopic methods and, in the case of 2, by X-ray crystallography. The water-soluble nido-carboranylporphyrin 5 (H(2)OCP) was found to have low dark toxicity toward V79 lung fibroblasts (CS(50) > or = 250 microM), to be readily taken up by human glioblastoma T98G cells in culture and to localize subcellularly preferentially in the cell lysosomes. In comparison with a known tetra(nido-carboranyl)porphyrin (6), H(2)OCP (5) is taken up slower and to a lower extent by T98G cells, possibly as a result of its higher hydrophilic character. The metal-free H(2)OCP (5) was also found to accumulate to a higher extent in T98G cells compared with its zinc(II) complex analog 4. Our studies show that carboranylporphyrins bearing eight nido-carborane cages can still accumulate intracellularly and have low dark toxicity toward cells in culture, and therefore might have promise for application in BNCT.
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PMID:Synthesis and cellular studies of an octa-anionic 5,10,15,20-tetra[3,5-(nido-carboranylmethyl)phenyl]porphyrin (H(2)OCP) for application in BNCT. 1569 81

The blood-brain barrier (BBB) regulation is characterized by an interplay between endothelial cells, subendothelial basal laminae and astrocytic cells. Astroglial cells are highly polarized by the differentiation of perivascular membrane domains. These domains are characterized by the aggregation of, among other molecules, the water channel protein aquaporin-4 (AQP4), the dystrophin-dystroglycan complex, and the inwardly rectifying potassium channel protein Kir4.1. Normally, this ion channel plays an important role in spatial buffering of extracellular K(+) in the central nervous system, which only can be performed due to the non-uniform distribution of Kir4.1 across the surface of the glial cell. In this study, we observed a mislocalization of Kir4.1 in various human brain tumors (low- and high-grade astrocytomas and oligodendrogliomas), suggesting that buffering capacity of glial cells may be compromised, leading to water influx (cytotoxic edema). Interestingly, whereas dystrophin remained regularly restricted at the endfeet membranes in all cases investigated, AQP4 was found to be redistributed only in high-grade astrocytomas, not in low-grade astrocytomas. If the mechanisms of redistribution of AQP4 and Kir4.1 are different in low- and high-grade gliomas, this may suggest that the mechanisms of clustering of AQP4 and Kir4.1 at the glial endfeet membrane domains are also different. The redistribution of AQP4 in glioblastoma cells is discussed as a reaction to the vasogenic edema, as induced by the breakdown of the BBB, to facilitate reabsorption of excess fluid.
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PMID:Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors. 1572 36

Boron neutron capture therapy (BNCT) is an adjuvant therapy that has the potential to control local tumor growth. A selective delivery of sufficient amounts of boron to individual tumor cells, compared to surrounding normal tissues, is the key for successful BNCT. We have designed and synthesized a new highly water-soluble boronated porphyrin, TABP-1, as a possible BNCT agent. When we injected the maximum tolerated dose (MTD: 15 mg/kg) of TABP-1 systemically into the tail vein of athymic rats bearing intracerebral (i.c.) human glioblastoma U-87 MG xenografts, the compound accumulated preferentially in brain tumors compared to normal brain; however, the level of boron in the tumors was less than the 30 microg/g of tissue that is generally considered necessary for BNCT. We next investigated whether convection-enhanced delivery (CED) could improve the boron distribution. The compound was administered directly into i.c. tumors using an osmotic minipump attached to a brain-infusion cannula. TABP-1 doses from 0.25 to 1.0 mg infused locally over 24 h produced tumor boron concentrations greater than those obtained by systemic administration at the MTD. For example, CED administration of 0.5 mg of TABP-1 produced a tumor boron level of 65.4 microg/g of tumor, whereas the serum level was only 0.41 microg/g (tumor to serum ratio of approximately 160:1). CED also produced relatively high tumor to normal brain ratios of approximately 5:1 for ipsilateral brain and approximately 26:1 for contralateral brain tissues at the 0.5 mg dose. Thus, we may be able to achieve therapeutic BNCT efficacy with minimal systemic toxicity or radiation-induced damage to normal tissue by administering TABP-1 using CED.
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PMID:In vivo evaluation of the boronated porphyrin TABP-1 in U-87 MG intracerebral human glioblastoma xenografts. 1602 7

Human malignant brain tumors have a poor prognosis in spite of surgery and radiation therapy. Cubic phases consist of curved biocontinuous lipid bilayers, separating two congruent networks of water channels. Used as a host for cytotoxic drugs, the gel-like matrix can easily be applied to the walls of a surgical resection cavity. For human glioblastoma recurrences, the feasibility, safety, and short-term effects of a surgical intracavitary application of paclitaxel and carboplatin encapsulated by liquid crystalline cubic phases are examined in a pilot study. A total of 12 patients with a recurrence of a glioblastoma multiforme underwent re-resection and received an intracavitary application of paclitaxel and carboplatin cubic phases in different dosages. Six of the patients received more than 15 mg paclitaxel and suffered from moderate to severe brain edema, while the remaining patients received only a total of 15 mg paclitaxel. In the latter group, brain edema was markedly reduced and dealt medically. Intracavitary chemotherapy in recurrent glioblastoma using cubic phases is feasible and safe, yet the clinical benefit remains to be examined in a clinical phase II study.
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PMID:Intracavitary chemotherapy (paclitaxel/carboplatin liquid crystalline cubic phases) for recurrent glioblastoma -- clinical observations. 1613 24

A water-soluble nido-carboranyl-tetrabenzoporphyrin has been synthesized in 43% overall yield, by condensation of butanopyrrole with a carboranylbenzaldehyde, followed by metal insertion, oxidation, demetallation and deboronation reactions. This compound accumulated within human glioblastoma T98G cells to a significant higher extent than a structurally related nido-carboranylporphyrin, and localized preferentially in the cell lysosomes. Animal toxicity studies using male and female BALB/c mice revealed that both compounds are non-toxic even at a dose of 160 mg/kg, administered intraperitoneally as a single injection at a concentration of 4 mg/mL. It is concluded that the tetra(carboranylphenyl)-tetrabenzoporphyrin is a promising new sensitizer for the treatment of malignant tumors.
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PMID:Synthesis, cellular uptake and animal toxicity of a tetra(carboranylphenyl)-tetrabenzoporphyrin. 1629 34

Therapeutic agents for brain tumors confront multiple physical and metabolic hurdles. These include the blood brain barrier (BBB), vascular and interstitial barriers, clearing by MDR1 and other ABC transporter proteins, and drug catabolism. Here, we report an accumulation of gefitinib in glioblastoma (GBM) tissue to over a dozen times plasma levels, and propose that some mechanisms converge to achieve such accumulation: (1) small molecular size of gefitinib facilitates access by diffusion; (2) its high water solubility enables thermodynamic retention inside malignant cells; and (3) low CYP3A4 activity in GBM tissue, the main enzyme for gefitinib catabolism, prevents metabolic elimination. Our data confirm the capacity of gefitinib to accumulate in solid human tumors in vivo.
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PMID:Gefitinib accumulation in glioblastoma tissue. 1658 94

This report introduces a novel method to characterize the diffusion-time dependence of the diffusion-weighted magnetic resonance (MR) signal in biological tissues. The approach utilizes the theory of diffusion in disordered media where two parameters, the random walk dimension and the spectral dimension, describe the evolution of the average propagators obtained from q-space MR experiments. These parameters were estimated, using several schemes, on diffusion MR spectroscopy data obtained from human red blood cell ghosts and nervous tissue autopsy samples. The experiments demonstrated that water diffusion in human tissue is anomalous, where the mean-square displacements vary slower than linearly with diffusion time. These observations are consistent with a fractal microstructure for human tissues. Differences observed between healthy human nervous tissue and glioblastoma samples suggest that the proposed methodology may provide a novel, clinically useful form of diffusion MR contrast.
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PMID:Observation of anomalous diffusion in excised tissue by characterizing the diffusion-time dependence of the MR signal. 1696 1


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