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)

Borocaptate sodium (BSH) and L-boronophenylalanine (L-BPA) are two boron carriers used for boron neutron capture therapy (BNCT) in the treatment of glioblastoma and melanoma, respectively. The suitability of these two compounds was evaluated on the basis of pharmacokinetic studies aiming at characterizing their biodistribution, tumor uptake and tumor selectivity. Boric acid was also used as a reference compound since it is nonselective and relatively freely diffusible. The compounds were investigated in two tumor models, a B16 pigmented melanoma and the RIF1 sarcoma. Mice were sacrificed after different boron doses at various post-injection times and tissue and plasma levels measured using inductively coupled plasma atomic emission spectroscopy (ICP-AES). The proposed minimum effective tumor boron concentration of 15 ppm was achieved in both tumor models for the three compounds tested, although only for L-BPA in the melanoma was this achieved when tumor-plasma ratios were above 1. In the RIF1 model, maximum tumor concentrations of 44 and 31 ppm B were reached after administration of 50 micrograms B/g body weight for boric acid and BSH, respectively. After administration of 12.5 micrograms B/g of L-BPA, maximum concentrations of 15 and 21 ppm were found in the RIF1 and B16 models, respectively. Tumor-plasma ratios (TPR) for BSH remained close to or below unity at all times studied in both tumors. Brain levels of BSH were very low, however, leading to tumor-brain ratios markedly greater than 1 at all times. L-BPA and boric acid showed TPR values above unity in both tumor models, reaching 3.2 in B16.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selectivity of boron carriers for boron neutron capture therapy: pharmacological studies with borocaptate sodium, L-boronophenylalanine and boric acid in murine tumors. 832 32

Neutron capture irradiation aims to selectively destroy tumor cells using 10B(n,alpha)7Li nuclear reactions produced within themselves. Following the capture reaction, an alpha particle and a, 7Li ion are emitted. Carrying an energy of 2.79 MeV, they destroy all molecular structures along their path close to 10 microns. These captures, used exclusively with a 'slow' neutron irradiation, provide a neutron capture therapy (BNCT). If they are used in addition to a fast neutron beam irradiation, they provide a neutron capture potentiation (NCP). The Centre Antoine-Lacassagne in Nice is actively involved in the European Demonstration Project for BNCT of grade IV glioblastomas (GBM) after surgical excision and BSH administration. Taking into account the preliminary results obtained in Japan, work on an 'epithermal' neutron target compatible with various cyclotron beams is in progress to facilitate further developments of this technique. For NCP, thermalized neutron yield has been measured in phantoms irradiated in the fast neutron beam of the biomedical cyclotron in Nice. A thermal peak appears after 5 cm depth in the tissues, delayed after the fast neutron peak at 1.8 cm depth. Thus, a physical overdosage of 10% may be obtained if 100 ppm of 10B are assumed in the tissues. Our results using CAL 58 GBM cell line demonstrate a dose modification factor (DMF) of 1.19 when 100 ppm of boric acid are added to the growth medium. Thus for the particles, issued from neutron capture, a biological efficiency at least twice that of fast neutrons can be derived. These results, compared with historical data on fast neutron irradiation of glioblastoma, suggest that a therapeutic window may be obtained for GBM.
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PMID:Boron neutron capture irradiation: setting up a clinical programme in Nice. 894 80

To plan the optimal BNCT using BSH for glioblastoma patients, the 10B concentration in tumor and blood was investigated in 11 newly diagnosed glioblastoma patients. All patients received 20 mg BSH/kg body weight 2.5-16 hrs prior to tumor removal. The quantitative distribution of 10B was determined by prompt gamma ray spectrometry and/or alpha-track autoradiography. 10B distribution in tumors was heterogeneous, +/- 25% of scattering at the microscopic level, and the distribution was also heterogeneous at the tissue level. 10B concentration in blood decreased in bi-exponential decay as a function of the time after the end of the administration. The T/B ratio showed non-exponential increase with large variation. The maximum T/B ratio would be around 1. The tumor/normal brain (T/N) ratio of 10B concentration was 11.0 +/- 3.2. The 10B content in normal brain is originated in vascular 10B in parenchyma, since the 10B content in normal brain to blood (N/B ratio) being compatible with the blood content in parenchyma. These values allow for BNCT, using thermal neutrons, on brain tumors located less than approximately 3.3 cm in depth from the brain surface of neutron incidence, providing that the dose on the normal endothelium is controlled to less than the tolerance limit. In our preliminary study of BNCT, a 31% 3-year survival was achieved over all for 16 glioblastoma patients and a 50% 2-year survival was achieved on 8 glioblastoma patients in our recent dose escalation study based on these data.
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PMID:Boron neutron capture therapy: preliminary study of BNCT with sodium borocaptate (Na2B1 2H1 1SH) on glioblastoma. 926 56

A number of carborane-containing porphyrins were administered to mice bearing subcutaneously transplanted mammary carcinomas. Administration was via serial intraperitoneal (i.p.) injections to assess their relative toxicities and tumour affinities. Three analogues of the natural porphyrin heme and four tetraphenylporphyrins (TPPs) were given at total doses of 78-245 micrograms g-1 body weight. The water-insoluble TPPs were less toxic to mice, and delivered greater amounts of boron to tumour than did the water-soluble TPPS and the heme analogues. One such compound, NiTCP-H, delivered more than 100 micrograms B g-1 to tumour tissue with a tumour:blood boron concentration ratio greater than 500:1 and a tumour: brain boron concentration ratio greater than 50:1, 4 days after the last of six i.p. injections given over 2 days. Another TPP analogue, NiTCP, delivered approximately 50 micrograms B g-1 to tumour with similar boron concentrations in normal tissues. Neither compound was toxic to mice at total doses of approximately 200 micrograms g-1 body weight. In contrast, the heme analogues were toxic and, with the exception of VCDP, delivered less boron to tumour than NiTCP and NiTCP-H. The two porphyrins with the greatest potential for application to boron neutron capture therapy (BNCT), NiTCP and NiTCP-H, yielded higher tumour:blood and tumour:brain boron concentration ratios in mice than could be achieved with p-boronophenylalanine (BPA) and sodium mercaptoundecahydrododecaborate (BSH), the compounds which are currently being used in clinical trials of BNCT in the treatment of glioblastoma. The boron delivered by each of the porphyrins tested remained in tumour tissue longer than did boron delivered by either BPA or BSH. The copper and nickel chelates of these porphyrins behave identically in vivo. The former offer the potential for imaging by 67Cu-mediated single photon emission computed tomography (SPECT) to aid BNCT treatment planning.
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PMID:Evaluation of carborane-containing porphyrins as tumour targeting agents for boron neutron capture therapy. 977 89

Boron neutron capture therapy (BNCT) is a targeted radiation therapy that significantly increases the therapeutic ratio relative to conventional radiotherapeutic modalities. BNCT is a binary approach: A boron-10 (10B)-labeled compound is administered that delivers high concentrations of 10B to the target tumor relative to surrounding normal tissues. This is followed by irradiation with thermal neutrons or epithermal neutrons which become thermalized at depth in tissues. The short range (5-9 microm) of the alpha and 7Li particles released from the 10B(n,alpha)7Li neutron capture reaction make the microdistribution of 10B of critical importance in therapy. The radiation field in tissues during BNCT consists of a mixture of components with differing LET characteristics. Studies have been carried out in both normal and neoplastic tissues to characterize the relative biological effectiveness of each radiation component. The distribution patterns and radiobiological characteristics of the two 10B delivery agents in current clinical use, the amino acid p-boronophenylalanine (BPA) and the sulfhydryl borane (BSH), have been evaluated in a range of normal tissues and tumor types. Considered overall, BSH-mediated BNCT elicits proportionately less damage to normal tissue than does BNCT mediated with BPA. However, BPA exhibits superior in vivo tumor targeting and has proven much more effective in the treatment of brain tumors in rats. In terms of fractionation effects, boron neutron capture irradiation modalities are comparable with other high-LET radiation modalities such as fast-neutron therapy. There was no appreciable advantage in increasing the number of daily fractions of thermal neutrons beyond two with regard to sparing of normal tissue in the rat spinal cord model. The experimental studies described in this review constitute the radiobiological basis for the new BNCT clinical trials for glioblastoma at Brookhaven National Laboratory, at the Massachusetts Institute of Technology, and at the High Flux Reactor, Petten, The Netherlands. The radiobiology of experimental and clinical BNCT is discussed in detail.
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PMID:The radiation biology of boron neutron capture therapy. 997 79

The boron neutron capture therapy is based on the reaction occurring between the isotope 10B and thermal neutrons. A low energy neutron is captured by the nucleus and it disintegrates into two densely ionising particles, Li nucleus and He nucleus (alpha particle), with high biological effectiveness. On the basis of comprehensive preclinical investigations in the frame of the European Collaboration with Na2B12H11SH (BSH), as boron delivery agent, the first European phase I, clinical trial was designed at the only available epithermal beam in Europe, at the High Flux Reactor, Petten, in the Netherlands. The goal of this study is to establish the safe BNCT dose for cranial tumors under defined conditions. BNCT is applied as postoperative radiotherapy in 4 fractions, after removal of the tumor for a group of patients suffering from glioblastoma, who would have no benefit from conventional treatment, but have sufficient life expectancy to detect late radiation morbidity due to BNCT. The starting dose is set at 80% of the dose where neurological effects occurred in preclinical large animal experiments following a single fraction. The radiation dose will be escalated, by constant boron concentration in blood, in 4 steps for cohorts of ten patients, after an observation period of at least 6 months after the end of BNCT of the last patient of a cohort. The adverse events on healthy tissues due to BSH and due to the radiotherapy will be analysed in order to establish the maximal tolerated dose and dose limiting toxicity. Besides of the primary aim of this study the survival will be recorded. The first patient was treated in October 1997, and further four patients have been irradiated to-date. The protocol design proved to be well applicable, establishing the basis for scientific evaluation, for performance of safe patient treatment in a very complex situation and for opening the possibility to perform further clinical research work on BNCT.
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PMID:Postoperative treatment of glioblastoma with BNCT at the petten irradiation facility (EORTC protocol 11,961). 1039 16

Boron neutron capture therapy (BNCT) is an experimental, binary treatment for brain cancer which requires as the first step that tumor tissue is targeted with a boron-10 containing compound. Subsequent exposure to a thermal neutron flux results in destructive, short range nuclear reaction within 10 microm of the boron compound. The success of the therapy requires than the BNCT agents be well localized in tumor, rather than healthy tissue. The MEPHISTO spectromicroscope, which performs microchemical analysis by x-ray absorption near edge structure (XANES) spectroscopy from microscopic areas, has been used to study the distribution of trace quantities of boron in human brain cancer tissues surgically removed from patients first administered with the compound Na2B12H11SH (BSH). The interpretation of XANES spectra is complicated by interference from physiologically present sulfur and phosphorus, which contribute structure in the same energy range as boron. We addressed this problem with the present extensive set of spectra from S, B, and P in relevant compounds. We demonstrate that a linear combination of sulfate, phosphate and BSH XANES can be used to reproduce the spectra acquired on boron-treated human brain tumor tissues. We analyzed human glioblastoma tissue from two patients administered and one not administered with BSH. As well as weak signals attributed to BSH, x-ray absorption spectra acquired from tissue samples detected boron in a reduced chemical state with respect to boron in BSH. This chemical state was characterized by a sharp absorption peak at 188.3 eV. Complementary studies on BSH reference samples were not able to reproduce this chemical state of boron, indicating that it is not an artifact produced during sample preparation or x-ray exposure. These data demonstrate that the chemical state of BSH may be altered by in vivo metabolism.
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PMID:Spectromicroscopy of boron in human glioblastomas following administration of Na2B12H11SH. 1108 67

A co-culture, cryogenic SIMS methodology is presented for the quantitative analysis of cell type-dependent accumulation of boron delivered by BPA-F and BSH, two clinically approved drugs used in boron neutron capture therapy of cancer. T98G human glioblastoma cells were co-cultured with morphologically different normal LLC-PK1 epithelial cells or GM3348 human skin fibroblasts. Our freeze-fracture method of cryogenic sample preparation successfully fractured the different cell types grown together in co-cultures. Quantitative observations revealed an active uptake of boron from BPA-F in both T98G and LLC-PK1 cells but did not show cell type-dependent differences. Accumulation of BSH in all three cell types examined also did not reveal any cell type-dependent differences in co-cultures. As this method relies on the analysis, within the same field of SIMS imaging, of two different cell types that have been maintained under identical conditions of growth, drug exposure, sample preparation, and instrumental analysis, it provides the most effective approach for comparing cell type-specific differences in boron concentrations. The most effective applications of this method will be realized in testing the selectivity of experimental boronated compounds designed to specifically target tumor cells.
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PMID:Dynamic secondary ion mass spectrometry analysis of boron from boron neutron capture therapy drugs in co-cultures: single-cell imaging of two different cell types within the same ion microscopy field of imaging. 1153 21

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

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


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