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Boron neutron capture therapy (BNCT) represents a highly promising therapeutic alternative for the treatment of the most common malignant brain tumor, glioblastoma multiforme. Both the efficacy and safety of BNCT are greatly dependent on the pattern of 10B biodistribution. The present study investigates the influence of systemic hyaluronidase applied in combination with Na2B12H11SH (BSH), a boron carrier used in current clinical trials. The application of hyaluronidase was associated with a statistically significant improvement in the tumor/blood boron concentration ratio which suggests that hyaluronidase is capable of enhancing the therapeutic potential of BSH.
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PMID:Boron neutron capture therapy for glioblastoma: improvement of boron biodistribution by hyaluronidase. 983 25

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 cell membrane permeability of 10B-enriched borocaptate sodium (BSH) and the extent to which BSH is accumulated in cells are controversial. To elucidate these points and to enhance the accumulation of BSH in cells, the effect of electroporation on boron neutron capture therapy (BNCT) using BSH was investigated. The first group of SCCVII tumor cells was incubated in culture medium with 10B-BSH or 10B-enriched boric acid, and exposed to neutrons from the heavy water facility of the Kyoto University Reactor. More than 99% of neutrons were thermal neutrons at flux base. The second group was pretreated with electroporation in combination with 10B-BSH, and thereafter the cells were irradiated with neutrons. The cell-killing effect of BNCT was measured by colony formation assay. The surviving cell fraction decreased exponentially with neutron fluence, and addition of BSH significantly enhanced the cell-killing effect of NCT depending on 10B concentration and the preincubation time of cells in the BSH-containing culture medium. The electroporation of cells with BSH markedly enhanced the BNCT effect in comparison with that obtained with preincubation alone. The effect of BSH-BNCT with electroporation was almost equal to that of BNCT using 10B-boric acid at the same 10B concentration. The effect of BNCT on cells pretreated with BSH and electroporation was not reduced by repeated washing of the cells before neutron irradiation. Decrease of the effect of BSH-BNCT plus electroporation with increase in the waiting time between the electroporation and the neutron irradiation could be explained in terms of the extent of cell growth during that time. These data suggest that BSH penetrates the cells slowly and remains after washing. Electroporation can introduce BSH into the cells very efficiently, and BSH thus introduced stays in the cells and is not lost in spite of the intensive washing of the cells. Therefore, if electroporation is applied to tumors after BSH injection, 10B would remain in the tumors but be cleared from normal tissues, and selective accumulation of 10B in tumors will be achieved after an appropriate waiting time.
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PMID:Effect of electroporation on cell killing by boron neutron capture therapy using borocaptate sodium (10B-BSH). 1008 97

The multiprotein complexes involved in active dis-ruption of chromatin structure, homologous to yeast SWI/SNF complex, have been described for human and Drosophila cells. In all SWI/SNF-class complexes characterised so far, one of the key components is the SNF5-type protein. Here we describe the isolation of a plant (Arabidopsis thaliana ) cDNA encoding a 27 kDa protein which we named BSH, with high homology to yeast SNF5p and its human (INI1) and Drosophila (SNR1) counterparts as well as to other putative SNF5-type proteins from Caenorhabditis elegans, fish and yeast. With 240 amino acids, the Arabidopsis BSH is the smallest SNF5-type protein so far identified. When expressed in Saccharomyces cerevisiae, the gene for BSH partially complements the snf5 mutation. BSH is, however, unable to activate transcription in yeast when tethered to DNA. The gene for BSH occurs in single copy in the Arabidopsis genome and is ubiquitously expressed in the plant. Analysis of the whole cell and nuclear protein extracts with antibodies against recombinant BSH indicates that the protein is localised in nuclei. Transgenic Arabidopsis plants with markedly decreased physiological level of the BSH mRNA, resulting from the expression of antisense messenger, are viable but exhibit a distinctive phenotype characterised by bushy growth and flowers that are unable to produce seeds.
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PMID:Identification and analysis of the Arabidopsis thaliana BSH gene, a member of the SNF5 gene family. 1032 30

Boron-containing compounds like closo-dodecaborate(2-) are in theory suitable for radioactive labeling with halogens. The boron-halogen bond is stronger than carbon-halogen bond and is not likely to be recognized by deiodinating enzymes in vivo. Peptides and proteins may be conjugated with various closo-dodecaborate(2-)-containing ligands, and thereafter, the conjugate can be iodinated. Since closo-dodecaborate(2-) is more avidly iodinated than tyrosine in moderately acidic media, such conjugates may be directly labeled on the boron part with radioisotopes of iodine using the standard Chloramine-T procedure. Mercapto-undecahydro-closo-dodecaborate(2-) (BSH) was reacted with the double bond of allyldextran to form a boronated dextran compound of the molecular size of about 70 kDa. This compound, in the text denoted as Dx-BS, and cesium dodecahydro-closo-dodecaborate(2-) were labeled using iodine-125. The two compounds were administered to rats in order to study their in vivo stability. The results indicate that iodinated Dx-BS is stable for about 20 h in vivo. The degradation rate, as indicated by thyroid uptake, was found low. [125I]Iodo-closo-dodecaborate(2-), which is a possible degradation product of [125I]Dx-BS-I, was rapidly excreted in urine without significant accumulation in any organ.
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PMID:Closo-dodecaborate(2-) as a linker for iodination of macromolecules. Aspects on conjugation chemistry and biodistribution. 1034 62

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

A new boronated porphyrin compound (STA-BX909) was developed as a possible agent for boron neutron capture therapy. The boron concentration was measured by an in vivo rat experimental brain tumor model and an in vitro cell culture study. This agent was compared to sodium borocaptate (BSH) which has been used in clinical trials of boron neutron capture therapy. In the 9L rat brain tumor model, STA-BX909 achieved a higher boron tumor/blood ratio 24 h after injection in comparison to BSH. A boron concentration study in cultured glioma cell lines (U-251, U-87, 9L) demonstrated an increased boron concentration as a function of exposure time to STA-BX909, while the boron concentration remained stable with increasing exposure time to BSH. Use of a colony forming assay with thermal neutron irradiation revealed more cytotoxicity with STA-BX909 than BSH when the same concentration of 10B was administered. We concluded that STA-BX909 may be an effective drug for use in boron neutron capture therapy and that it merits further investigation.
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PMID:A new boronated porphyrin (STA-BX909) for neutron capture therapy: an in vitro survival assay and in vivo tissue uptake study. 1045 63

A boron-enriched streptavidin has been prepared by chemical conjugation of a boron-rich compound, B(12)H(11)SH(2)(-) (BSH), to a genetically engineered streptavidin variant. The streptavidin variant used has 20 cysteine residues per molecule, derived from a C-terminal cysteine stretch consisting of five cysteine residues per subunit. Because natural streptavidin has no cysteine residues, the reactive sulfhydryl groups of the cysteine stretch serve as unique conjugation sites for sulfhydryl chemistry. BSH was conjugated irreversibly to the sulfhydryl groups of the streptavidin variant via a sulfhydryl-specific homobifunctional chemical cross-linker. Quantitative boron analysis indicates that the resulting streptavidin-BSH conjugate carries approximately 230 boron atoms/molecule. This indicates that the chemical conjugation of BSH to the streptavidin variant was highly specific and efficient because this method should allow the conjugation of a maximum of 240 boron atoms/streptavidin molecule. This boron-enriched streptavidin retained both full biotin-binding ability and tetrameric structure, suggesting that the conjugation of BSH has little, if any, effect on the fundamental properties of streptavidin. This boron-enriched streptavidin should be very useful as a component of targetable boron carriers for neutron capture therapy of cancer. For example, a monoclonal antibody against a tumor-associated antigen can be attached tightly to the boron-enriched streptavidin upon simple biotinylation, and the resulting conjugate could be used to target boron to tumor cells on which the tumor-associated antigen is overexpressed.
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PMID:Boron-enriched streptavidin potentially useful as a component of boron carriers for neutron capture therapy of cancer. 1050 60

The effects of bile salts on the survival of lactobacilli were investigated using glycocholic acid, cholic acid and deoxycholic acid as model compounds and the bile salt hydrolase active Lactobacillus plantarum 80 (BSH+) and its BSH negative mutant. The detrimental effects of cholic acid, i.e. growth inhibition and cytotoxicity at a concentration of 1 and 5 mmol l-1, respectively, were considered to be due to the hydrophobic protonated form of the molecule, which brings about membrane damage. The conversion of glycocholic acid to cholic acid by the BSH active L. plantarum 80 caused a growth inhibition which was comparable with the inhibition observed in the broth supplemented with 1 mmol l-1 cholic acid. Deoxycholic acid caused toxicity through membrane damage when the compound was in solution. Its toxicity disappeared in the culture broth as the molecule precipitated. In case of cholic acid, the toxicity could be removed by buffering the solution at pH 7.0. It was calculated that at this pH most of the cholic acid molecules were ionized. The results led to the formulation of an extended hypothesis about the ecological significance of bile salt transformations. Primary deconjugation is carried out to counteract intracellular acidification. Yet, the deconjugated molecule can be harmful at moderately acidic pH-values. In this case, the BSH+ strains could effectively profit from their activity in case they are associated with 7alpha-dehydroxylating bacteria which dehydroxylate the deconjugated bile salts. The dehydroxylated molecule has a low solubility and precipitates at moderately acidic pH.
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PMID:Bile salt deconjugation by lactobacillus plantarum 80 and its implication for bacterial toxicity 1054 Feb 35

The paper presents the results of the joint project carried out in Germany in order to assess the consequences in the marine environment from the dumping of nuclear wastes in the Kara and Barents Seas. The project consisted of experimental work on measurements of radionuclides in samples from the Arctic marine environment and numerical modelling of the potential pathways and dispersion of contaminants in the Arctic Ocean. Water and sediment samples were collected for determination of radionuclide such as 137Cs, 90Sr, 239 + 240Pu, 238Pu, and 241Am and various organic micropollutants. In addition, a few water and numerous surface sediment samples collected in the Kara Sea and from the Kola peninsula were taken by Russian colleagues and analysed for artificial radionuclide by the BSH laboratory. The role of transport by sea ice from the Kara Sea into the Arctic Ocean was assessed by a small subgroup at GEOMAR. This transport process might be considered as a rapid contribution due to entrainment of contaminated sediments into sea ice, following export from the Kara Sea into the transpolar ice drift and subsequent release in the Atlantic Ocean in the area of the East Greenland Current. Numerical modelling of dispersion of pollutants from the Kara and Barents Seas was carried out both on a local scale for the Barents and Kara Seas and for long range dispersion into the Arctic and Atlantic Oceans. Three-dimensional baroclinic circulation models were applied to trace the transport of pollutants. Experimental results were used to validate the model results such as the discharges from the nuclear reprocessing plant at Sellafield and subsequent contamination of the North Sea up the Arctic Seas.
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PMID:Anthropogenic radioactivity in the Arctic Ocean--review of the results from the joint German project. 1056 75


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