Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to improve the effectiveness of boron neutron capture therapy (BNCT) for malignant gliomas, we examined the optimization of the administration of boron compounds in brain tumor animal model. We analyzed the concentration of boron atoms in intracranial C6 glioma -bearing rats using inductively coupled plasma atomic emission spectrometry. Each tumor-bearing rat received one of two different amounts of sodium borocaptate (BSH) and/or 500 mg/kg of boronophenylalanine (BPA) via intraperitoneal injection. We compared the boron concentrations of the tumor, the contralateral normal brain and the blood in rats of 3 different treatment groups (BSH alone, BPA alone and a combination of both BSH and BPA). Our results show that the tumor boron concentration increased much more than 30 microg/g by the coadministration of both compounds. Additionally, the blood boron concentration remained below 30 microg/g and the boron concentration in the normal brain was low (mean 4.7+/-1.1 microg/g). Even in comparison with the administration of BPA alone, coadministration of BPA and BSH shows an improved tumor/normal brain ratio of boron concentrations.
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PMID:Pharmacokinetic study of BSH and BPA in simultaneous use for BNCT. 1655 51

We determined one mechanism by which the putative phosphoinositide-dependent kinase (PDK)-1 inhibitor 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}acetamide (OSU-03012) killed primary human glioma and other transformed cells. OSU-03012 caused a dose-dependent induction of cell death that was not altered by p53 mutation, expression of ERBB1 vIII, or loss of phosphatase and tensin homolog deleted on chromosome 10 function. OSU-03012 promoted cell killing to a greater extent in glioma cells than in nontransformed astrocytes. OSU-03012 and ionizing radiation caused an additive, caspase-independent elevation in cell killing in 96-h viability assays and true radiosensitization in colony formation assays. In a cell type-specific manner, combined exposure to OSU-03012 with a mitogen-activated protein kinase kinase 1/2 inhibitor, phosphoinositide 3-kinase/AKT inhibitors, or parallel molecular interventions resulted in a greater than additive induction of cell killing that was independent of AKT activity and caspase function. OSU-03012 lethality as a single agent or when combined with signaling modulators was not modified in cells lacking expression of BIM or of BAX/BAK. OSU-03012 promoted the release of cathepsin B from the lysosomal compartment and release of AIF from mitochondria. Loss of BH3-interacting domain (BID) function, overexpression of BCL(XL), and inhibition of cathepsin B function suppressed cell killing and apoptosis-inducing factor (AIF) release from mitochondria. In protein kinase R-like endoplasmic reticulum kinase-/- cells, the lethality of OSU-03012 was attenuated which correlated with reduced cleavage of BID and with suppression of cathepsin B and AIF release into the cytosol. Our data demonstrate that OSU-03012 promotes glioma cell killing that is dependent on endoplasmic reticulum stress, lysosomal dysfunction, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways.
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PMID:OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells. 1662 74

3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (compound 1, N5-2OH) belongs to a novel class of boron delivery agents for neutron capture therapy, which was designated 3-carboranylthymidine analogue (3CTAs). Two shorter and more convenient synthetic routes were developed for the synthesis of 1 in the 10B-enriched form, which is necessary for its preclinical and clinical evaluation in neutron irradiation studies. For more insight on structure-activity relationships, various stereochemical and geometrical isomers of 1 were synthesized and their specificities as substrate for human thymidine kinase 1 (hTK1) were evaluated. A computational model for the binding of various isomers of 1 to the active site of hTK1 was developed. Preliminary studies carried out in F98 glioma bearing rats that had received a 10B-enriched form of 1 followed by neutron irradiation demonstrated a significant prolongation in survival times compared to control animals, suggesting that further studies are warranted to evaluate the therapeutic potential of 1.
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PMID:Preparation and biological evaluation of 10B-enriched 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH), a new boron delivery agent for boron neutron capture therapy of brain tumors. 1694 24

The objective of the present study was to construct epidermal growth factor receptor (EGFR) targeting cetuximab-immunoliposomes (ILs) for targeted delivery of boron compounds to EGFR(+) glioma cells for neutron capture therapy. The ILs were synthesized by using a novel cholesterol-based membrane anchor, maleimido-PEG-cholesterol (Mal-PEG-Chol), to incorporate cetuximab into liposomes by either surface conjugation or a post-insertion method. For post-insertion, the transfer efficiency of MAb conjugates from micelles to liposome was examined at varying temperatures, mPEG2000-DSPE ratios, and micelle-to-liposome lipid ratios. Following this, the cetuximab-ILs were evaluated for targeted delivery of the encapsulated boron anion, dodecahydro-closo-dodecaborate (2-) (B12H122-), to human EGFR gene transfected F98EGFR glioma cells as potential delivery agents for boron neutron capture therapy (BNCT). In addition, cellular uptake of cetuximab-ILs, encapsulating a fluorescence dye, was analyzed by confocal fluorescence microscopy and flow cytometry, and boron content was quantified by ICP-MS. Much greater ( approximately 8-fold) cellular uptake of boron was obtained using cetuximab-ILs in EGFR(+) F98EGFR compared with nontargeted human IgG-ILs. On the basis of these observations, we have concluded that cholesterol can serve as an effective anchor for MAb in liposomes, and cetuximab-ILs are potentially useful delivery vehicles for BNCT of gliomas.
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PMID:Synthesis of cetuximab-immunoliposomes via a cholesterol-based membrane anchor for targeting of EGFR. 1722 62

Boron neutron capture therapy (BNCT) is an experimental technique for the treatment of certain kinds of tumors. Research in BNCT is performed utilizing both thermal and epithermal neutron beams. Epithermal neutrons (0.4 eV-10 keV) penetrate more deeply into tissue and are thus used in non-superficial clinical applications such as the brain glioma. In the last few years, the fast reactor TAPIRO (ENEA-Casaccia Rome) has been employed as a neutron source for research into BNCT applications. Recently, an 'epithermal therapeutic column' has been designed and its construction has been completed. The Monte Carlo code MCNPX was employed to optimize the design of the column and to evaluate the dose profiles and the therapeutic parameters in the cranium of the anthropomorphic phantom ADAM. In the same context, some preliminary evaluations of the undesirable doses to the patient were performed with MCNPX. A hermaphrodite phantom derived from ADAM and EVA was employed to evaluate the energy deposition in some organs during a standard BNCT treatment. The total dose consists of the contributions from the primary neutron beam, the neutron interactions with boron and the neutron induced photons generated in the epithermal column structures and in the patient's tissues. The paper summarizes the computational procedure and provides a general dosimetric framework of the patient radiological protection aspects related to a BNCT treatment scenario at the TAPIRO reactor.
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PMID:Preliminary evaluations of the undesirable patient dose from a BNCT treatment at the ENEA-TAPIRO reactor. 1770 5

The major aim of this study was to develop novel therapeutic approaches to potentiate and reactivate apoptosis induced by TNF-Related Apoptosis Inducing Ligand (TRAIL) in malignant glioma. Analysis of five glioma cell lines (U87, U251, U373, MZ-54 and MZ-18) indicated that only two of the cell lines were sensitive to apoptosis induced by TRAIL alone. TRAIL resistance was not correlated to expression levels of the death receptors DR4 and DR5 or the decoy receptors DcR1 and DcR2, suggesting that it was mediated by inactivation of TRAIL-induced downstream signalling. Activation of the BH3 only protein Bid and subsequent activation of the mitochondrial apoptosis pathway are known to play a pivotal role in TRAIL-induced apoptosis. Since this process is blocked by overexpression of anti-apoptotic Bcl-2 family members, we analyzed the therapeutic potential of BH3 mimetics in potentiating TRAIL-induced apoptosis. Treatment with TRAIL in combination with the specific Bcl-2 inhibitor HA14-1 and the Bcl-2/Bcl-xL inhibitor BH3I-2' potently enhanced apoptosis in TRAIL-sensitive U87 cells in a dose-dependent fashion. TRAIL-induced apoptosis was significantly reactivated by HA14-1 and BH3I-2' in one (U343) and two (MZ-54 and MZ-18) of three investigated TRAIL-insensitive cell lines, respectively. Knockdown of the anti-apoptotic Bcl-2 family member Mcl-1 by RNA interference had no additional effect on apoptosis induced by TRAIL and HA14-1 in U87 and U343 cells. Our data indicate that Bcl-2 and Bcl-xL play fundamental roles in TRAIL resistance of malignant glioma and suggest that using TRAIL or agonistic TRAIL receptor antibodies in combination with BH3 mimetics may represent a promising approach to reactivate apoptosis in therapy-resistant high grade gliomas.
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PMID:Pharmacological inhibition of Bcl-2 family members reactivates TRAIL-induced apoptosis in malignant glioma. 1792 59

Early effects of boron neutron capture therapy (BNCT) on malignant glioma are characterized by reduction of the enhancement area and regression of the peritumoral edema radiologically. The aim of this study was to investigate the early histological changes of tumors and inflammatory cells after BNCT in the rat brain. Rats were treated with BNCT using boronophenylalanine (BPA) 7 days after implantation of C6 glioma cells. The tumors were assessed with magnetic resonance imaging and histopathological examination at 4 days after BNCT. The mean tumor volumes were 39 +/- 2 mm3 in the BNCT group and 134 +/- 18 mm3 in the control group. In the BNCT group, tumor cells showed a less pleomorphic appearance with atypical nuclei and mitotic figures. The Ki-67 labeling index was 6.5% +/- 4.7% in the BNCT and 35% +/- 3.8% in the control group. The reactions of the inflammatory cells were examined with ED-1 as macrophage marker and OX42 as microglia marker. ED-1- and OX-42-positive cells were reduced both in the core and the marginal area of the tumor in the BNCT group. It is suggested that BNCT reduced tumor progression by suppression of proliferation. Inhibition of the activated macrophages may relate to reduced peritumoral edema in the early phase.
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PMID:Early effects of boron neutron capture therapy on rat glioma models. 1809 38

Boron neutron capture therapy (BNCT) theoretically allows the preferential destruction of tumor cells while sparing the normal tissue, even if the cells have microscopically spread to the surrounding normal brain. The tumor cell-selective irradiation used in this method is dependent on the nuclear reaction between the stable isotope of boron ((10)B) and thermal neutrons, which release alpha and (7)Li particles within a limited path length (-9 microm) through the boron neutron capture reaction, (10)B(n,alpha)(7)Li. Recent clinical studies of BNCT have focused on high-grade glioma and cutaneous melanoma; however, cerebral metastasis of melanoma, anaplastic meningioma, head and neck tumor, and lung and liver metastasis have been investigated as potential candidates for BNCT. To date, more than 350 high-grade gliomas have been treated in BNCT facilities worldwide. Current clinical BNCT trials for glioblastoma (GBM) have used the epithermal beam at a medically optimized research reactor, and p-dihydroxyboryl-phenylalanine (BPA) and/or sulfhydryl borane Na(2)B(12)H(11)SH (BSH) as the boron delivery agent(s). The results from these rather small phase I/II trials for GBM appear to be encouraging, but prospective randomized clinical trials will be needed to confirm the efficacy of this theoretically promising modality. Improved tumor-targeting boron compounds and optimized administration methods, improved boron drug delivery systems, development of a hospital-based neutron source, and/or other combination modalities will enhance the therapeutic effectiveness of BNCT in the future.
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PMID:Boron neutron capture therapy for glioblastoma. 1831 7

Boron neutron capture therapy (BNCT) is a binary radiation therapy used to treat malignant brain tumours. It is based on the nuclear reaction (10B + n th --> [11B*] --> alpha + 7Li + 2.79 MeV) that occurs when 10B captures a thermal neutron to yield alpha particles and recoiling 7Li nuclei, both responsible of tumour cells destruction by short range and high ionization energy release. The clinical success of the therapy depends on the selective accumulation of the 10B carriers in the tumour and on the high thermal neutron capture cross-section of 10B. Magnetic resonance imaging (MRI) methods provide the possibility of monitoring, through 10B nuclei, the metabolic and physiological processes suitable to optimize the BNCT procedure. In this study, spatial distribution mapping of borocaptate (BSH) and 4-borono-phenylalanine (BPA), the two boron carriers used in clinical trials, has been obtained. The BSH map in excised rat brain and the 19F-BPA image in vivo rat brain, representative of BPA spatial distribution, were reported. The BSH image was obtained by means of double-resonance 10B-editing 1H-detection sequence, named M-Bend, exploiting the J-coupling interaction between 10B and 1H nuclei. Conversely, the BPA map was obtained by 19F-BPA using 19F-MRI. Both images were obtained at 7 T, in C6 glioma-bearing rat brain. Our results demonstrate the powerful of non conventional MRI techniques to optimize the BNCT procedure.
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PMID:10B-editing 1H-detection and 19F MRI strategies to optimize boron neutron capture therapy. 1848 94

Here, we investigated the specific roles of Bcl-2 family members in anoxia tolerance of malignant glioma. Flow cytometry analysis of cell death in 17 glioma cell lines revealed drastic differences in their sensitivity to oxygen withdrawal (<0.1% O(2)). Cell death correlated with mitochondrial depolarization, cytochrome C release, and translocation of green fluorescent protein (GFP)-tagged light chain 3 to autophagosomes but occurred in the absence of caspase activation or phosphatidylserine exposure. In both sensitive and tolerant glioma cell lines, anoxia caused a significant up-regulation of BH3-only genes previously implicated in mediating anoxic cell death in other cell types (BNIP3, NIX, PUMA, and Noxa). In contrast, we detected a strong correlation between anoxia resistance and high expression levels of antiapoptotic Bcl-2 family proteins Bcl-xL, Bcl-2, and Mcl-1 that function to neutralize the proapoptotic activity of BH3-only proteins. Importantly, inhibition of both Bcl-2 and Bcl-xL with the small-molecule BH3 mimetics HA14-1 and BH3I-2' and by RNA interference reactivated anoxia-induced autophagic cell death in previously resistant glioma cells. Our data suggest that endogenous BH3-only protein induction may not be able to compensate for the high expression of antiapoptotic Bcl-2 family proteins in anoxia-resistant astrocytomas. They also support the conjecture that BH3 mimetics may represent an exciting new approach for the treatment of malignant glioma.
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PMID:BH3 mimetics reactivate autophagic cell death in anoxia-resistant malignant glioma cells. 1867 Jun 45


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