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)

Like most cells in culture, stably transfected COS-1 cells (CF18) that constitutively overexpress basic fibroblast growth factor (FGF2) do not release the growth factor into conditioned media. Yet, when cells were biotinylated, 30% of the total cell-associated immunoreactive FGF2 was detected on the cell surface. Under similar conditions, up to 70% of the total immunoreactive FGF2 in transfected endothelial cells (MAE ZIP) or untransfected rat (C6) and human (U87MG) glioblastoma cell lines was detected on their cell surface. When peripheral plasma membrane proteins were removed from the cell surface with 0.1 M sodium carbonate, the amount of exported FGF2 was significantly reduced, whereas cell viability was unaffected. FGF2 then reappeared on the cell surface in a time-dependent manner. Ouabain, a cardenolide previously shown to inhibit the export of FGF2 from transiently transfected COS-1 cells, blocked the appearance of FGF2 onto the surface of transfected CF18 cells and MAE ZIP cells but had no detectable effect on C6 and U87MG cells. The observation that the translocation of FGF2 onto the cell surface is dissociated from its release into conditioned medium is consistent with FGF2's being rarely found in biological fluids but always cell associated and in the extracellular matrix. The findings point to a role played by the protein export pathway in controlling FGF2 activity and the normal physiological function that this growth factor plays in cell growth and differentiation. The widely accepted presumption that the absence of FGF2 in conditioned media reflects its inability to exit the cell needs to be reevaluated.
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PMID:Translocation of FGF2 to the cell surface without release into conditioned media. 1102 48

The aim of this study was to evaluate the role of bcl-2 in 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) sensitivity of the ADFS human glioblastoma cell line in vitro and in vivo. To this end, the ADFS line expressing a low level of the bcl-2 protein was transfected with a bcl-2 expression vector. We found that bcl-2 overexpressing clones were less sensitive to in vitro BCNU treatment than the control clone. Cell cycle analysis demonstrated that while BCNU induced a consistent block in S/G2-M phases of the cell cycle in the control clone, it did not affect the cell cycle phase distribution of the two bcl-2 transfectants. The different sensitivity to BCNU was unrelated to the ability of bcl-2 to inhibit apoptosis, while bcl-2 appeared to protect bcl-2 transfectants from BCNU toxicity through an increase of catalase activity. The ability of the catalase inhibitor, sodium azide, to increase the BCNU sensitivity of the bcl-2 transfectants to levels of the BCNU-treated control clone substantiated the role of the catalase activity. The effect of bcl-2 in reducing sensitivity to BCNU was also confirmed by in vivo experiments. Xenografts of bcl-2 overexpressing tumors were less sensitive to BCNU treatment than xenografts originating from control cells.
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PMID:Bcl-2 overexpression decreases BCNU sensitivity of a human glioblastoma line through enhancement of catalase activity. 1159 15

Heat shock proteins (HSPs) are immediately expressed in neuronal and glial cells under various stressful conditions and play a protective role through molecular chaperones. We investigated the characteristics of the induction manner of heme oxygenase-1 (HO-1) and HSP70 in rat C6 glioblastoma cells. In heat treatment (42 degrees C for 30 min), C6 cells expressed high level of HO-1 and HSP70 mRNAs within 30-60 min, and their proteins at 3 hrs. Heat-induced expressions of HSPs mRNAs were completely inhibited with actinomycin D, suggesting the transcriptional regulation. Oxygen-glucose deprivation (OGD), cystine-free (inhibition of synthesis of glutathione), cyto-toxic (ethanol, sodium butyrate) treatments resulted in different expression manners between HO-1 and HSP70, which suggested that HO-1 and HSP70 play different protective roles against a variety kind of stressful conditions in glial cells. C6 cells can differentiate toward both astrocyte and oligodendrocyte directions. Treatment with dibutyryl cyclic AMP (cAMP) induces expression of glial fibrillary acidic protein (GFAP), a marker of astrocytes, and treatment with retinoic acid (RA) induces expression of myelin proteolipid protein (PLP), a marker of oligodendrocytes, respectively. Heat treatment before the initiation of differentiation by RA reduced the RA-induced expression of PLP mRNA profoundly, but not in GFAP mRNA level induced by cAMP. Heat treatment after the initiation of differentiation by cAMP or RA accelerated the expression of GFAP or PLP mRNAs. Astroglial differentiation by cAMP reduced the heat-induced expressions of HSPs mRNAs, but no change with RA pre-treatment. These results suggested that HSPs may modulate the glial differentiation in the developing brain. On the contrary, glial differentiation may give influence on the stress-induced HSPs expression. The timing of stressful damages, resulting in the expression of HSPs, on the developing brain is critically important for the pathogenesis of glial lesion. In the heat-treated C6 cells, the expression of platelet-derived growth factor (PDGF) receptor-alpha mRNA was significantly decreased. HSPs may have ability to induce the glial differentiation in part through down-regulation of the PDGF pathway.
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PMID:Induction of heat shock proteins and its effects on glial differentiation in rat C6 glioblastoma cells. 1159 26

Ion microscopy was used for subcellular quantitative imaging of the isotopes 10B and 11B in the same cell to evaluate boron delivery using a mixture of two neutron capture therapy drugs, p-boronophenylalanine-fructose (BPA-F) and sodium borocaptate (BSH). The application of 10B-labeled BPA-F and 11B-labeled BSH allowed independent imaging of both 10B and 11B in the same cell using a CAMECA IMS-3f ion microscope. Mixed-drug treatments were compared to single-drug exposures given under identical conditions. 10BPA-F delivered 10B heterogeneously to T98G human glioblastoma cells, with a significantly reduced concentration in an organelle-rich perinuclear region. The intracellular distribution of 11B from 11BSH contrasted with that of the 10B from 10BPA-F, with 11B distributed nearly homogeneously throughout cells. The subcellular distributions of 10B and 11B were sustained in mixed-drug treatments and resembled their localizations after the single-drug treatments. In both single- and mixed-drug treatments, cellular levels of 10B from 10BPA-F nearly doubled between 1 h and 6 h, with a 3:1 intracellular to nutrient medium partitioning, while cellular levels of 11BSH remained essentially unchanged. The net effect of the combined treatment with 10BPA-F and 11BSH was an additive delivery of boron to cells. This study introduces a novel approach for checking potential synergistic, antagonistic or simple additive delivery of two mixed boronated compounds in cellular/subcellular compartments.
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PMID:Quantitative subcellular secondary ion mass spectrometry (SIMS) imaging of boron-10 and boron-11 isotopes in the same cell delivered by two combined BNCT drugs: in vitro studies on human glioblastoma T98G cells. 1200 50

The sodium/iodide symporter (NIS) has been recognized as an attractive target for radioiodine-mediated cancer gene therapy. In this study we investigated the role of human NIS for cellular uptake of the high LET alpha-emitter astatine-211 ((211)At) in comparison with radioiodine as a potential radionuclide for future applications. A mammalian NIS expression vector was constructed and used to generate six stable NIS-expressing cancer cell lines (three derived from thyroid carcinoma, two from colon carcinoma, one from glioblastoma). Compared with the respective control cell lines, steady state radionuclide uptake of NIS-expressing cell lines increased up to 350-fold for iodine-123 ((123)I), 340-fold for technetium-99m pertechnetate ((99m)TcO(4)(-)) and 60-fold for (211)At. Cellular (211)At accumulation was found to be dependent on extracellular Na(+) ions and displayed a similar sensitivity towards sodium perchlorate inhibition as radioiodide and (99m)TcO(4)(-) uptake. Heterologous competition with unlabelled NaI decreased NIS-mediated (211)At uptake to levels of NIS-negative control cells. Following uptake both radioiodide and (211)At were rapidly (apparent t(1/2) 3-15 min) released by the cells as determined by wash-out experiments. Data of scintigraphic tumour imaging in a xenograft nude mice model of transplanted NIS-modified thyroid cells indicated that radionuclide uptake in NIS-expressing tumours was up to 70 times ((123)I), 25 times ((99m)TcO(4)(-)) and 10 times ((211)At) higher than in control tumours or normal tissues except stomach (3-5 times) and thyroid gland (5-10 times). Thirty-four percent and 14% of the administered activity of (123)I and (211)At, respectively, was found in NIS tumours by region of interest analysis ( n=2). Compared with cell culture experiments, the effective half-life in vivo was greatly prolonged (6.5 h for (123)I, 5.2 h for (211)At) and preliminary dosimetric calculations indicate high tumour absorbed doses (3.5 Gy/MBq(tumour) for (131)I and 50.3 Gy/MBq(tumour) for (211)At). In conclusion, NIS-expressing tumour cell lines of different origin displayed specific radionuclide uptake in vitro and in vivo. We provide first direct evidence that the high-energy alpha-emitter (211)At is efficiently transported by NIS. Application of (211)At may direct higher radiation doses to experimental tumours than those calculated for (131)I. Thus, (211)At may represent a promising alternative radionuclide for future NIS-based tumour therapy.
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PMID:Establishment of radioactive astatine and iodine uptake in cancer cell lines expressing the human sodium/iodide symporter. 1211 Nov 24

We investigated the effects of histone deacetylase (HDAC) inhibitors such as sodium butyrate (SB) and trichostatin A (TSA) on the expression of vascular endothelial growth factor (VEGF) by human glioblastoma T98G, U251MG, and U87MG cells. The glioblastoma cells secreted three VEGF isoforms, VEGF (189), (165), and (121), although the expression levels of VEGF differed between the cell types. Treatment with either 5mM SB or 100 ng/ml TSA reduced VEGF secretion in conditioned media and reduced VEGF mRNA expression. We also studied the expression of VEGF-B, -C, and -D mRNA in human glioblastoma cells and their modulation by HDAC inhibitors. The PCR products of VEGF-B (357bp), VEGF-C (501bp), and VEGF-D (484bp) were amplified in all glioblastoma cells examined. Treatment with SB reduced the expression of VEGF-D mRNA in U251MG cells and the expression of VEGF-B mRNA in U87MG cells. TSA treatment reduced the expression of VEGF-D in U251MG cells. These results suggest that HDAC inhibitors reduce VEGF secretion and modulate the expression of the other VEGF family members, and therefore may inhibit angiogenesis in glioblastoma tissues.
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PMID:Histone deacetylase inhibitors such as sodium butyrate and trichostatin A inhibit vascular endothelial growth factor (VEGF) secretion from human glioblastoma cells. 1262 37

We very effectively treated two patients with recurrent glioblastoma with modified boron neutron capture therapy (BNCT). In this paper, we describe the effectiveness of this treatment, and discuss the ways in which we modified the treatment. A 61-year-old man had a first operation for a right temporal glioblastoma, followed by full-dose chemo-radiotherapy. One year after the operation a partial removal was performed for the recurrent tumor at the same site. Fifty days after the second surgery, the patient received BNCT. We used an epithermal neutron beam as the neutron source, and used both sodium borocapate and boronophenylalanine as boron compounds with the craniotomy. Forty-eight hours after the BNCT, the follow-up MRI was applied to estimate the early effect of this treatment, which showed a 70% reduction in the contrast enhanced lesion, compared with the pretreatment MRI. In addition, the lesion/normal brain ratio of thallium-SPECT had improved markedly. No serial sequelae appeared after this treatment, and the patient remains healthy 6 months after the treatment. A 29-year-old young lady had a right temporal brain tumor, which was partially resected and followed by stereotactic radiosurgery for the residual mass. Seven months after the radiosurgery, a second operation was performed, which revealed the glioblastoma as diagnosis. We applied BNCT uneventfully for this patient with epithermal beam and two kinds of boron compounds as described above. For the treatment of the patient irradiation was applied without craniotomy with marked reduction of tumor volume immediately after the treatment.
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PMID:The early successful treatment of glioblastoma patients with modified boron neutron capture therapy. Report of two cases. 1468 36

The radiopharmaceutical 3-[(123)I]iodo-alpha-methyl-L-tyrosine ([(123)I]IMT) can be used to study amino acid transport by single-photon emission tomography (SPET). In order to evaluate the potential contribution of [(123)I]IMT accumulation in macrophages to overall uptake values measured in neoplastic lesions in vivo, we studied the mechanisms governing the uptake of this tracer by human monocyte-macrophages (HMMs). HMMs were isolated from healthy human donors by density gradient centrifugation using Ficoll methods. The human glioblastoma cell line U-138 MG (GLIOs) was obtained from American Type Culture Collection. Using multiwell dishes, cells were incubated in phosphate buffered saline or an equivalent sodium-free buffer with 50 kBq [(131)I]IMT per well. [(131)I]IMT uptake was quantified as % injected dose per mass of protein within each culture well. Several natural and artificial amino acids were used as potential transport inhibitors both in sodium-containing and sodium-free medium. [(131)I]IMT uptake was significantly lower in HMMs than in GLIOs (34 +/- 2 %/mg (40 min) vs. 507 +/- 50 %/mg at 30 minutes of incubation, respectively; p < 0.01). Endotoxin (LPS) significantly increased [(131)I]IMT uptake in HMMs by a factor of approximately 2. Transport into non-stimulated HMMs was exclusively sodium-independent and inhibitable by BCH, but not by MeAIB. Under LPS stimulation exclusively, there was in addition also a sodium-dependent inhibition of [(131)I]IMT uptake by L-arginine and MeAIB, albeit to a minor extent. [(131)I]IMT accumulation in HMMs is mainly mediated via an L-like amino acid transport system and increases on HMM activation by LPS. LPS may induce an additional Na(+)-dependent transport system in HMMs. The considerably lower [(131)I]IMT uptake in HMMs than in GLIOs suggests that overall uptake values of this tracer measured by SPET in tumors are not significantly affected by [(123)I]IMT accumulation in macrophages within the neoplastic lesion.
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PMID:Characterization of uptake of 3-[(131)I]iodo-alpha-methyl-L-tyrosine in human monocyte-macrophages. 1502 49

Since 1998, we have introduced a mixed epithermal- and thermal neutron beam for boron neutron capture therapy (BNCT) to improve the neutron beam distribution. Sixteen patients with malignant glioma (glioblastoma, n = 14; anaplastic ependymoma, n = 1; PNET, n = 1) were treated by BNCT in Japan. Of these, 9 died; 3 due to cerebrospinal fluid (CSF) dissemination, 1 each of tumor invasion, meningitis, pneumonia, and unknown causes, and 2 patients died of local recurrence or radiation necrosis. The current postmortem study is comprised of 3 patients with glioblastoma who were treated with BNCT employing an epithermal neutron beam and sodium borocaptate (BSH: Na2B12H11SH). None of the patients manifested local regrowth at the primary site. However, in 2 patients there was CSF dissemination; tumor cells were recognized throughout the subarachnoid space. In the other patient, tumor cells had massively invaded the ipsilateral- and contralateral hemisphere and brain stem from the bottom of the tumor cavity via the corpus callosum and cerebral peduncle. Our findings indicate that BNCT can achieve local control of glioblastoma at the primary site. However, to further improve the clinical outcome after BNCT, steps must be taken to prevent CSF dissemination.
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PMID:Histopathological findings in autopsied glioblastoma patients treated by mixed neutron beam BNCT. 1517 18

The purpose of this study was to clarify the radiation injury in acute or delayed stage after boron neutron capture therapy (BNCT) using mixed epithermal- and thermal neutron beams in patients with malignant glioma. Eighteen patients with malignant glioma underwent mixed epithermal- and thermal neutron beam and sodium borocaptate between 1998 and 2004. The radiation dose (i.e. physical dose of boron n-alpha reaction) in the protocol used between 1998 and 2000 (Protocol A, n = 8) prescribed a maximum tumor volume dose of 15 Gy. In 2001, a new dose-escalated protocol was introduced (Protocol B, n = 4); it prescribes a minimum tumor volume dose of 18 Gy or, alternatively, a minimum target volume dose of 15 Gy. Since 2002, the radiation dose was reduced to 80-90% dose of Protocol B because of acute radiation injury. A new Protocol was applied to 6 glioblastoma patients (Protocol C, n = 6). The average values of the maximum vascular dose of brain surface in Protocol A, B and C were 11.4+/-4.2 Gy, 15.7+/-1.2 and 13.9+/-3.6 Gy, respectively. Acute radiation injury such as a generalized convulsion within 1 week after BNCT was recognized in three patients of Protocol B. Delayed radiation injury such as a neurological deterioration appeared 3-6 months after BNCT, and it was recognized in 1 patient in Protocol A, 5 patients in Protocol B. According to acute radiation injury, the maximum vascular dose was 15.8+/-1.3 Gy in positive and was 12.6+/-4.3 Gy in negative. There was no significant difference between them. According to the delayed radiation injury, the maximum vascular dose was 13.8+/-3.8 Gy in positive and was 13.6+/-4.9 Gy in negative. There was no significant difference between them. The dose escalation is limited because most patients in Protocol B suffered from acute radiation injury. We conclude that the maximum vascular dose does not exceed over 12 Gy to avoid the delayed radiation injury, especially, it should be limited under 10 Gy in the case that tumor exists in speech center.
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PMID:Radiation injury of boron neutron capture therapy using mixed epithermal- and thermal neutron beams in patients with malignant glioma. 1530 93


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