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)

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

Nine high grade gliomas (5 glioblastomas and 4 anaplastic astrocytomas) were treated with BSH-based intaoperative boron neutron capture therapy (IOBNCT). BSH (100 mg/kg body weight) was intravenously injected, followed by single fraction irradiation using the mixed thermal/epithermal beam of Japan Research Reactor 4. The blood boron level at the time of irradiation averaged 29.9 (18.8-39.5)microg/g. The peak thermal neutron flux as determined by post-irradiation measurements varied from 1.99 to 2.77x10(9) n cm(-2)s(-1). No serious BSH-related toxicity was observed in this series. The interim survival data in this study showed median survival times of 23.2 months for glioblastoma and 25.9 months for anaplastic astrocytoma, results which are consistent with the current conventional radiotherapy with/without boost radiation. Of the 4 residual tumors, 2 showed complete response (CR) and 2 showed partial response (PR) within 6 months following BNCT. No linear correlation was proved between the dose and the occurrence of early neurological events. The maximum boron dose of 11.7-12.2 Gy in the brain related to the occurrence of radiation necrosis. The clinical application of a mixed thermal/epithermal beam and JRR-4 facilities on BSH-based IOBNCT proved to be safe and effective in this series.
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PMID:Current clinical results of the Tsukuba BNCT trial. 1530 97

A study of the (10)B-enriched p-boronophenylalanine-fructose complex ((10)BPA-F) infusion procedure in potential BNCT patients, including four melanoma of extremities and two high-grade gliomas (glioblastoma and ganglioglioma) was performed. T/B and S/B ratios for (10)B concentrations in tumor (T), blood (B) and skin (S) were determined. The T/B ratio for the glioblastoma was in the 1.8-3.4 range. The ganglioglioma did not show any significant boron uptake. For the nodular metastasic melanoma T/B values were between 1.5 and 2.6 (average 2.1+/-0.4), corresponding to the lower limit of the mean values reported for different melanoma categories. This result might suggest a lower boron uptake for nodular metastasic melanomas. S/B was 1.5+/-0.4. An open two-compartment pharmacokinetic model was applied to predict the boron concentration during the course and at the end of a BNCT irradiation.
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PMID:Biodistribution studies of boronophenylalanine-fructose in melanoma and brain tumor patients in Argentina. 1530 98

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

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

Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also interacts and forms complexes with proteins important in extracellular matrix organization and cellular adhesion. We have identified the novel finding that treatment of glioblastoma cells with transglutaminase 2 inhibitors promotes cell death and enhances sensitivity to chemotherapy. Treatment with either the competitive transglutaminase 2 inhibitor, monodansylcadaverine, or with highly specific small-molecule transglutaminase 2 inhibitors, KCA075 or KCC009, results in induction of apoptosis in glioblastoma cells. Treatment with these transglutaminase 2 inhibitors resulted in markedly decreased levels of the prosurvival protein, phosphorylated Akt, and its downstream targets. These changes promote a proapoptotic profile with altered levels of multiple intracellular proteins that determine cell survival. These changes include decreased levels of the antiapoptotic proteins, survivin, phosphorylated Bad, and phosphorylated glycogen synthetase kinase 3beta (GSK-3beta), and increased levels of the proapoptotic BH3-only protein, Bim. In vivo studies with s.c. murine DBT glioblastoma tumors treated with transglutaminase 2 inhibitors combined with the chemotherapeutic agent, N-N'-bis (2-chloroethyl)-N-nitrosourea (BCNU), decreased tumor size based on weight by 50% compared with those treated with BCNU alone. Groups treated with transglutaminase 2 inhibitors showed an increased incidence of apoptosis determined with deoxynucleotidyl transferase-mediated biotin nick-end labeling staining. These studies identify inhibition of transglutaminase 2 as a potential target to enhance cell death and chemosensitivity in glioblastomas.
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PMID:Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas. 1617 20

Gliosarcoma, a rare pathological entity composed of 2-8% malignant gliomas, is characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. Here we report the preferential recurrence of a sarcomatous component in gliosarcoma after boron neutron capture therapy (BNCT), while a gliomatous component disappeared as a result of the treatment. A 56-year-old woman with a left frontal tumor was introduced to our clinic. After stereotactic biopsy, craniotomy was applied and 90% of the mass was resected. The histological diagnosis was glioblastoma with small amounts of sarcomatous component, that is, gliosarcoma. BNCT was applied 30 days after craniotomy. Two weeks after BNCT, almost all of the contrast-enhanced mass had disappeared on magnetic resonance images; however, a half year later, the mass recurred just below the original site and extended posteriorly. Irrespective of repetitive salvage surgeries, the patient died of the recurrent tumor. At autopsy, tumor cells of the frontal lobe were absent. A well-circumscribed mass of the parietal and occipital lobes was composed of sarcomatous material, with very little glial fibrillary acid protein-positive glial material. We found in this patient the preferential recurrence of the sarcomatous component of a gliosarcoma after potent radiotherapeutics in the form of BNCT.
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PMID:Preferential recurrence of a sarcomatous component of a gliosarcoma after boron neutron capture therapy: case report. 1623 87

A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal antibodies (MABs) that would be used as vehicles to transport the nontoxic agent to cancer cells. The anti HER-2 MABs have been successful in targeting HER-2 positive breast cancers with high affinity. The proposed concept would utilize a neutral nontoxic boron-10 predicting that anti HER-2 MABs would assure its selective delivery to cancer cells. MABs against HER-2 have been a widely researched strategy in the clinical setting. The most promising antibody is Trastuzumab (Herceptin). Targeting HER-2 with the MAB Trastuzumab has been proven to be a successful strategy in inducing tumour regression and improving patient survival. Unfortunately, these tumours become resistant and afflicted women succumb to breast cancer. In the proposed concept, when the tumour region is loaded with boron-10 it is irradiated with neutrons (treatment used for head and neck cancers, melanoma and glioblastoma for over 40 years in Japan and Europe). The irradiation process takes less than an hour producing minimal side effects. This paper summarizes our recent theoretical assessments of radiation binary targeted therapy for HER-2 positive breast cancers on: the effective drug delivery mechanism, the numerical model to evaluate the targeted radiation delivery and the survey study to find the neutron facility in the world that might be capable of producing the radiation effect as needed. A novel method of drug delivery utilizing Trastuzumab is described, followed by the description of a computational Monte Carlo based breast model used to determine radiation dose distributions. The total flux and neutron energy spectra of five currently available neutron irradiation treatment facilities are examined for this application. The tumour boron concentrations and tumour to healthy tissue concentration ratios required to deliver 50 Gy-Eq to the tumour without exceeding 18 Gy-Eq in the skin are determined, as well as the associated therapeutic ratios. Discussion is provided to address the future research direction for assessing the feasibility of the proposed concept.
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PMID:Radiation binary targeted therapy for HER-2 positive breast cancers: assumptions, theoretical assessment and future directions. 1651 Sep 50

For short range high linear energy transfer (LET) radiation therapy the biological effects are strongly affected by the heterogeneity of the specific energy (z) distribution delivered to tumour cells. Three-dimensional (3-D) dosimetry information at the cellular level is required for this study. An ideal approach would be the reconstruction of the cell and the radiation source microdistribution from sequential autoradiographic sections, which is, however, not a practical solution. In this paper, a novel microdosimetry analysis method, which obtains the specific energy (z) distribution directly from the morphological information in individual autoradiographic sections, is applied to human glioblastoma multifore (GBM) and normal brain tissue specimens in boron neutron capture therapy. The results are consistent with Monte Carlo simulation and demonstrate a uniform radiation source distribution in both GBM and normal brain tissues. We also hypothesise a biophysical model based on specific energy for survival analysis. The specific energy distributions to cell nuclei were calculated with a uniform radiation source distribution. By combining this microdosimetric analysis with measured cell survival data at the low dose region, a cell survival curve at high doses is predicted, which is consistent with the commonly used simple exponential curve model for high LET radiation.
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PMID:Microdosimetric analysis for high LET radiation. 1727 97

Boron measurements at subcellular scale are essential in boron neutron capture therapy (BNCT) of cancer as the nuclear localization of boron-10 atoms can enhance the effectiveness of killing individual tumour cells. Since tumours contain a heterogeneous population of cells in interphase as well as in the M phase (mitotic division) of the cell cycle, it is important to evaluate the subcellular distribution of boron in both phases. In this work, the secondary ion mass spectrometry (SIMS) based imaging technique of ion microscopy was used to quantitatively image boron from two BNCT agents, clinically used p-boronophenylalanine (BPA) and 3-[4-(o-carboran-1-yl)butyl]thymidine (N4), in mitotic metaphase and interphase human glioblastoma T98G cells. N4 belongs to a class of experimental BNCT agents, designated 3-carboranyl thymidine analogues (3CTAs), which presumably accumulate selectively in cancer cells due to a process referred to as kinase-mediated trapping (KMT). The cells were exposed to BPA for 1 h and N4 for 2 h. A CAMECA IMS-3f SIMS ion microscope instrument capable of producing isotopic images with 500 nm spatial resolution was used in the study. Observations were made in cryogenically prepared fast frozen, and freeze-fractured, freeze-dried cells. Three discernible subcellular regions were studied: the nucleus, a characteristic mitochondria-rich perinuclear cytoplasmic region, and the remaining cytoplasm in interphase T98G cells. In metaphase cells, the chromosomes and the cytoplasm were studied for boron localization. Intracellular concentrations of potassium and sodium also were measured in each cell in which the subcellular boron concentrations were imaged. Since the healthy cells maintain a K/Na ratio of approximately 10 due to the presence of Na-K-ATPase in the plasma membrane of mammalian cells, these measurements provided validation for cryogenic sample preparation and indicated the analysis healthy, well preserved cells. The BPA-treated interphase cells revealed significantly lower concentrations of boron in the perinuclear mitochondria-rich cytoplasmic region as compared to the remaining cytoplasm and the nucleus, which were not significantly different from each other. In contrast, the BPA-treated metaphase cells revealed significantly lower concentration of boron in their chromosomes than cytoplasm. In addition, the cytoplasm of metaphase cells contained significantly less boron than the cytoplasm of interphase cells. These observations provide valuable information on the reduced uptake of boron from BPA in mitotic cells for BPA-mediated BNCT. SIMS observations on N4 revealed that boron was distributed throughout the interphase and mitotic cells, including the chromosomes. The presence of boron in chromosomes of metaphase cells treated with N4 is indicative of a possible incorporation of this thymidine analogue into DNA. The 3-D SIMS imaging approach for the analysis of mitotic cells shown in this work should be equally feasible to the evaluation of other BNCT agents.
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PMID:Quantitative subcellular imaging of boron compounds in individual mitotic and interphase human glioblastoma cells with imaging secondary ion mass spectrometry (SIMS). 1817 48


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