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PubMed1999

Performance of silicon microdosimetry detectors in boron neutron capture therapy.

Reverse-biased silicon p-n junction arrays using Silicon-On-Insulator technology have been proposed as microdosimeters. The performance of such detectors in boron neutron capture therapy (BNCT) is discussed. This work provides the first reported measurements using boron-coated silicon diode arrays as microdosimeters in BNCT. Results are in good agreement with measurements with gas proportional counters. Various boron-coating options are investigated along with device orientation effects. Finally, a 235U coating is tested to simulate the behavior of the device in a heavy-ion therapy beam.

Boron↗
PubMed1993

Radiobiological considerations concerning the development of compounds for boron neutron capture therapy.

An analysis is carried out to evaluate the suitability of compounds for boron neutron capture therapy (BNCT). Suitable boron compounds are not necessarily those that show a high uptake ratio between tumor and healthy tissue. Compounds with lower uptake ratios, but higher concentrations in both healthy tissue and tumor, can be as effective in increasing the dose to the tumor over that of healthy tissue. In compound synthesis and evaluation, the parameters for optimization should therefore not be limited to the uptake ratio. A final assessment of the question whether and how well a given compound is suitable for BNCT can only be made after a study of its radiobiological effects on tissue. The analysis also illustrates the importance of beam quality in thermal and epithermal BNCT. An increase of adventitious radiation must be compensated by higher absolute tissue levels of a given boron compound and/or a higher uptake ratio, in order to arrive at the same dose differential between tumor and healthy tissue.

Boron Compounds↗
PubMed1997

Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption.

The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy could be enhanced by means of intracarotid (i.c.) injection of sodium borocaptate (BSH) or boronophenylalanine (BPA) with or without blood-brain barrier disruption (BBB-D). For biodistribution studies, F98 glioma-bearing rats were injected i.v. or i.c. with either BSH (30 mg of boron/kg of body weight) or BPA (24 mg of boron/kg of body weight) with or without mannitol-induced, hyperosmotic BBB-D and killed 2.5 h later. The highest tumor boron concentrations for BSH and BPA were attained following i.c. injection with BBB-D (48.6 and 94.0 microg/g, respectively) compared to i.c. (30.8 and 42.7 microg/g) and i.v. injection (12.9 and 20.8 microg). Using the same doses of BSH and BPA, therapy experiments were initiated 14 days after intracerebral implantation of F98 glioma cells. Animals were irradiated 2.5 h after i.v. or i.c. administration of the capture agent with or without BBB-D using a collimated beam of thermal neutrons at the Brookhaven Medical Research Reactor. The median survival times of rats given BSH or BPA i.c. were 52 and 69 days, respectively, for rats with BBB-D; 39 and 48 days for rats without BBB-D; 33 and 37 days for i.v. injected rats; 29 days for irradiated controls; and 24 days for untreated controls. i.c. injection of either BSH or BPA resulted in highly significant enhancement (P = 0.01 and P = 0.0002, respectively) of survival times compared to i.v. injection, and this was further augmented by BBB-D (P = 0.02 and P = 0.04, respectively) compared to i.c. injection. Normal brain tissue tolerance studies were carried out with non-tumor-bearing rats, which were treated in the same way as tumor-bearing animals. One year after irradiation, the brains of these animals showed only minimal radiation-induced changes in the choroid plexus, but no differences were discernible between irradiated controls and those that had BBB-D followed by i.c. injection of either BSH or BPA. Our data clearly show that the route of administration, as well as BBB-D, can enhance the uptake of BSH and BPA, and, subsequently, the efficacy of boron neutron capture therapy.

Alpha Particles↗
PubMed1997

Cytotoxicity and subcellular localization of boronated phenanthridinium analogues.

Binding and toxicity of boronated phenanthridinium analogues were studied in vitro using cultured human malignant glioma cells. The compounds, 5-ortho- (5-o-CP), 5-para- (5-p-CP), 5-nido- (5-n-CP) and 6-nido-carboranyl phenanthridinium (6-n-CP) showed varying toxic effects. The cells were exposed to the compounds for 2 or 24 h. The span between non-toxic and toxic concentrations seemed to be very narrow. 5-p-CP was the most toxic compound, causing total cell death at a concentration of 5 micrograms/ml cell culture medium. None of the compounds showed toxic effects at a concentration of 1 microgram/ml. Viable cells incubated with the compounds at this concentration showed a > 100-fold accumulation of boron. Only approximately 1/4 of this accumulation was found in cells permeabilized and inactivated with acetone. Fluorescent images of acetone-treated cells showed clear uptake of the compounds in the cell nucleus, as for ethidium bromide, while for viable cells binding to structures other than DNA was also observed. These results were confirmed by subcellular boron determination. All tested compounds intercalate into DNA, as was demonstrated in cell-free systems with calf thymus DNA. The hypothesis is that the compounds are trapped in the cellular membranes of viable cells because of their lipophilicity, before reaching nuclear DNA.

Boron↗
PubMed1998

The compound factor of the 10B(n,alpha)7Li reaction from borocaptate sodium and the relative biological effectiveness of recoil protons for induction of brain damage in boron neutron capture therapy.

To make clinical trials of boron neutron capture therapy safe for patients, it is necessary to know the relative biological effectiveness (RBE) of the radiation components and the compound factor of the boron carrier to be used. Here a method is derived to determine the RBE of recoil protons and the compound factor of compounds from in vivo experiments with different concentrations of boron. The method uses a simultaneous fit of both these parameters to all experimental data. This method is applied to the studies of tolerance of healthy tissue in dogs at the High Flux Reactor in Petten, The Netherlands. The RBE for the recoil protons generated by the neutrons present in the epithermal neutron beam [together with the RBE of the protons from the 14N(n,p)14C reaction] for induction of severe neurological symptoms was found to be 3.93+/-0.43 (95% confidence limits 3.06-4.79), and 2.33+/-0.14 (2.04-2.61) for induction of changes detectable by magnetic resonance imaging. The compound factor for Na2B12H11SH in brain tissue, using severe neurological symptoms as end point, was determined to be 0.37+/-0.06 (95% confidence limits 0.24-0.50). For changes detectable by magnetic resonance imaging, the value was found to be 0.65+/-0.04 (0.58-0.73).

Animals↗
PubMed1994

Production of no-carrier-added 64Cu from zinc metal irradiated under boron shielding.

BACKGROUND: Positron emission tomography offers advantages for radioimmunodiagnosis of cancer but requires radionuclides of appropriate half-life that have high specific activity and high radio-purity. This work was designed to develop a viable method to produce and purify 64Cu, which has high specific activity, for positron emission tomography. METHODS: 64Cu was produced at the University of Missouri Research Reactor by the nuclear reaction, 64Zn(n,p)64Cu. Highly pure zinc metal (99.9999%) was irradiated in a specially designed boron nitrite lined container, which minimized thermal neutron reactions during irradiation. A new two-step procedure was developed to chemically separate the no-carrier-added 64Cu from the zinc metal target. RESULTS: 64Cu recovery for 24 runs averaged 0.393 (+/- 0.007) mCi per milligram of zinc irradiated. The boron-lined irradiation container reduced unwanted zinc radionuclides 14.3-fold. Zinc radionuclides and non-radioactive zinc were separated successfully from the 64Cu. The new separation technique was fast (2 hours total time) and highly efficient for removing the zinc. The zinc separation factor for this technique averaged 8.5 x 10(-8), indicating less than 0.0000085% of the zinc remained after separation. Thus far, the highest 64Cu specific activity at end of irradiation was 683 Ci/mg Cu, with an average of 512 Ci/mg Cu for the last six analyzed runs. CONCLUSION: The boron-lined irradiation container has sufficient capacity for 75-fold larger-sized zinc targets (up to 45 g). The new separation technique was excellent for separating 64Cu, which appears to be a radionuclide with great potential for positron emission tomography.

Boron↗
PubMed1992

Synthesis, cytotoxicity, hypolipidemic and anti-inflammatory activities of amine-boranes and esters of boron analogues of choline and thiocholine.

Boron analogues of carbamoylcholine and thiocholine and esters of these analogues were prepared. These compounds were fairly stable toward hydrolysis and demonstrated moderate anti-inflammatory and hypolipidemic activities in mice. The hypolipidemic activity of the compounds at a dose of 8 mg/kg/day was equivalent in reducing lipid levels in serum to those of clofibrate at 150 mg/kg/day and lovastatin at 8 mg/kg/day. The compounds demonstrated significant cytotoxic activity against the growth of murine and human tumor cells; all were active against the growth of human HeLa-S3 uterine suspended cells, and some were active against murine L1210 lymphoid leukemia, human Tmolt3 leukemia cells, colorectal adenocarcinoma, KB nasopharynx, osteosarcoma, and glioma. These studies demonstrated that antimetabolite analogues of acetylcholine exhibit the same types of pharmacological activity as other boron-substituted betaine and amino acids. Furthermore, a strong positive correlation exists between hypolipidemic activity and cytotoxicity for these new choline derivatives, as has previously been demonstrated for other boron-containing amino acids, amides, esters, and peptides.

Amines↗
PubMed1998

Purification of thymine glycol DNA and nucleosides by use of boronate chromatography.

Boronate columns can be used to purify DNAs containing cis-thymine glycol residues and can also be used to purify cis-thymine glycol nucleosides. The boronate group can form a reversible complex with the cis-diol of the thymine glycol but not with the urea residue which is formed by alkaline hydrolysis of the thymine glycol. This method is rapid and appears applicable to a range of nucleic acids. In addition to the purifications of DNAs and nucleosides demonstrated here boronate chromatography may be applicable to assaying the extent and sites of oxidative damage to DNAs.

Boron Compounds↗
PubMed1997

The effects of dietary boron on bone strength in rats.

Previous studies from our laboratory found that when boric acid (BA) was administered in the diet to rats, boron levels in bone were approximately fourfold greater than serum levels. The current studies were undertaken to determine if these elevations produced adverse effects on several bone-related measures, including serum electrolyte levels, bone structure, and bone strength. Data from two studies are presented: in the first study, young adult male rats consumed a powdered diet containing 0, 3000, 4500, 6000, or 9000 ppm BA for 9 weeks. Endpoints were serum calcium, phosphorous, potassium, and chloride, as well as blood and bone boron concentrations ([B]) measured weekly during the 9-week exposure period, and at 8, 16, 24, and 32 weeks after the end of exposure. In the second study, the male and female young adult rats diet contained 0, 200, 1000, 3000, or 9000 ppm BA for 12 weeks; endpoints measured weekly were serum levels of calcium, phosphorous, and magnesium, bone [B], and bone structure (humerus) and strength (tibia, femur, and lumbar vertebrae). In treated rats, calcium was reduced in the first study but not the second. Serum phosphorous was reduced in both studies; potassium was unchanged, chloride was increased by 1%, and magnesium was reduced in all BA-exposed groups in the second study, to a maximal 19% reduction. Bone [B] was consistently increased in all treated groups, to concentrations approximately fourfold those of serum. After cessation of exposure, serum and urinary boron concentrations dropped to within control values within a week. However, even 32 weeks after the end of exposure, bone [B] remained threefold greater than controls. Male tibia and femur resistance to bending was unchanged. However, vertebral strength in compression was significantly increased by 5-10% in all dose groups (200 to 9000 ppm). The pattern was substantially similar in females. Only the humerus was examined by light microscopy and was found to be unchanged at any level of BA consumption. These data show that, despite a reduction in some serum electrolyte levels, BA consumption increased vertebral resistance to crush force, without detectably altering the microscopic structure of the humerus or the resistance of femur and tibia to a bending load. This increase in compression resistance occurred at exposure levels substantially below those that were previously reported to be reproductively toxic.

Animals↗
PubMed1990

Biomedical irradiation system for boron neutron capture therapy at the Kyoto University Reactor.

Physics studies related to radiation source, spectroscopy, beam quality, dosimetry, and biomedical applications using the Kyoto University Reactor Heavy Water Facility are described. Also, described are a Nickel Mirror Neutron Guide Tube and a Super Mirror Neutron Guide Tube that are used both for the measurement of boron concentration in phantom and living tissue and for precise measurements of neutron flux in phantom in the presence of both light and heavy water. Discussed are: (1) spectrum measurements using the time of flight technique, (2) the elimination of gamma rays and fast neutrons from a thermal neutron irradiation field, (3) neutron collimation without producing secondary gamma rays, (4) precise neutron flux measurements, dose estimation, and the measurement of boron concentration in tumor and its periphery using guide tubes, (5) the dose estimation of boron-10 for the first melanoma patient, and (6) special-purpose biological irradiation equipment. Other related subjects are also described.

Biophysical Phenomena↗
PubMed1988

Experience of boron-neutron capture therapy for malignant brain tumours--with special reference to the problems of postoperative CT follow-ups.

Boron-neutron capture therapy (BNCT) is theoretically a highly selective treatment of infiltrating tumours, in that the tumoricidal heavy particle radiation is limited to a sphere of 10 microns around a tumour cell which is loaded with non-radioactive boron-10 atoms. There were 73 gliomas among the 83 cases treated by boron-neutron capture therapy. For grade III-IV cerebral gliomas, 5 and 10 year survival rates were an unimpressive 19 and 10% respectively. This was the result of technical problems such as unsatisfactory reactors and inadequate craniotomies for the majority of the patients. If the analysis was limited to those whose tumours had been irradiated with more than 2.5 x 10(12) neutrons/cm2 (yielding more than 3,000 rem or more), the 5 and 10 year survival were almost 100 and 50%. The longest surviving glioblastoma (grade IV) patient has lived in a satisfactory manner for the past 15 years. For the cases who had been treated with borderline doses (lethal or sublethal), interpretation of the postoperative CTs was frequently intriguing. Several cases had to undergo re-opening and occasionally even another BNCT, only to find no viable tumour tissue. Death occurred in some, either due to discontinuation of supportive treatments by local physicians, or due to excessive therapies by the author directly involved in the patient's care, both of whom had erroneously believed in recurrence. At autopsy, residual tumour cells were recognized only in the areas where the above-mentioned neutron fluence had not been delivered at the time of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

A critical assessment of boron neutron capture therapy: an overview.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with neutrons of the appropriate energy to produce high-energy alpha particles and recoiling lithium-7 nuclei. BNCT has been used clinically to treat patients with high-grade gliomas, and a much smaller number with primary and metastatic melanoma. The purpose of this special issue of the Journal of Neuro-Oncology is to provide a critical and realistic assessment of various aspects of basic and clinical BNCT research in order to better understand its present status and future potential. Topics that are covered include neutron sources, tumor-targeted boron delivery agents, brain tumor models to assess therapeutic efficacy, computational dosimetry and treatment planning, results of clinical trails in the United States, Japan and Europe, pharmacokinetic studies of sodium borocaptate and boronophenylalanine (BPA), positron emission tomography imaging of BPA for treatment planning, and finally an overview of the challenges and problems that must be faced if BNCT is to become a useful treatment modality for brain tumors. Clinical studies have demonstrated the safety of BNCT. The next challenge is an unequivocal demonstration of therapeutic efficacy in one or more of the clinical trails that either are in progress or are planned over the next few years.

Animals↗
PubMed2003

Crystal structure of Enterobacter cloacae 908R class C beta-lactamase bound to iodo-acetamido-phenyl boronic acid, a transition-state analogue.

The structures of the class C beta-lactamase from Enterobacter cloacae 908R alone and in complex with a boronic acid transition-state analogue were determined by X-ray crystallography at 2.1 and 2.3 A, respectively. The structure of the enzyme resembles those of other class C beta-lactamases. The structure of the complex with the transition-state analogue, iodo-acetamido-phenyl boronic acid, shows that the inhibitor is covalently bound to the active-site serine (Ser64). Binding of the inhibitor within the active site is compared with previously determined structures of complexes with other class C enzymes. The structure of the boronic acid adduct indicates ways to improve the affinity of this class of inhibitors. This structure of 908R class C beta-lactamase in complex with a transition-state analogue provides further insights into the mechanism of action of these hydrolases.

Apoenzymes↗
PubMed2005

Boron neutron capture therapy for glioblastoma multiforme.

AIM: Glioblastoma multiforme (GBM) is an incurable disease that can only be managed in a palliative way. The GBM accounts for approximately half of all newly diagnosed primary brain tumors with an incidence of 2-3 cases per 100,000 people each year. Surgery and radiation are the standard options for palliation, and whether there is a place for chemotherapy is still discussed. Boron neutron capture therapy (BNCT) is a promising and possibly curative method of treating GBM. The purpose of this article is to provide an updated review on the current management and future possibilities of treating GBM with BNCT. METHOD: Use was made of computerized searches and of checking cross-references of articles and book chapters. RESULTS: The principle of BNCT uses the high ability of 10B to capture thermal neutrons and to disintegrate immediately into a He nucleus (alpha-particle) and a Li nucleus. To reach a sufficient concentration of 10B in the malignant cells compared to the surrounding healthy tissue, 10B-carriers must be highly tumor-selective. At present, the 10B carriers boronophenylalanine (BPA) and sodium borocaptate (BSH) are used in clinical trials to perform BNCT. CONCLUSION: The BNCT is a promising and possibly curative method of treating GBM, but at present this procedure is far from perfect. Because of the lack of selectivity of the boron carriers, it appears so far that radiation toxicity limits the radiation dose, so that tumor damage is modest. Current investigations and developments are aimed at targeting the boron carriers to the tumor, in order to limit the damage to the healthy, surrounding tissue.

Boron Neutron Capture Therapy↗
PubMed1983

Evaluation of immobilized boronates for studies of adenine and pyridine nucleotide metabolism.

Three different immobilized boronates were compared with respect to their possible utility in studies of adenine and pyridine nucleotide metabolism. These included boronate derivatives of polyacrylamide, Sepharose, and the cation-exchange resin, Bio-Rex 70. The relative binding affinities, binding capacities, and elution properties were compared. Under the conditions utilized, the Sepharose and Bio-Rex 70 derivatives selectively retained nucleotides containing two or more sets of 1,2 cis-diol groups. Since the bulk of cellular nucleic acids contain but a single set of 1,2 cis-diol groups or less, these boronate derivatives are very useful for the isolation of the acid-soluble nucleotides, NAD and diadenosine 5',5"'-tetraphosphate, and for the acid-insoluble polymer, poly(ADP-ribose). The Bio-Rex 70 derivative had a particularly useful combination of binding selectivity, capacity, and elution characteristics. Specific applications of this resin for studies of NAD and poly(ADP-ribose) metabolism are presented.

Adenine Nucleotides↗
PubMed1985

Assay of diadenosine tetraphosphate hydrolytic enzymes by boronate chromatography.

A new procedure was described for assay of diadenosine tetraphosphate (Ap4A) hydrolases based on boronate chromatography. Potential reaction products, AMP, ADP, and ATP, of the hydrolysis of Ap4A were separated from residual substrate by chromatography on a boronate-derivatized cation-exchange resin, Bio-Rex 70. Separation was achieved by changing the concentrations of ethanol and ammonium acetate in the elution buffers. Picomole masses of products were detectable, blank dpm values were less than 0.5% of the total dpm, and auxiliary enzymes were not required. The procedure was specifically described for Ap4A pyrophosphohydrolase from Physarum polycephalum. The assay is generally applicable for dinucleoside polyphosphate hydrolases which hydrolyze other substrates such as Ap3A, Ap5A, Ap6A, and Gp4G. Dinucleotide polyphosphates are readily purified by chromatography on this boronate resin in a volatile buffer. Tes, Tricine, and Tris buffers significantly interfered with the chromatography of ATP.

Acid Anhydride Hydrolases↗
PubMed1982

Inhibition of lipoprotein lipase by benzene boronic acid. Effect of apolipoprotein C-II.

The catalytic mechanism of triacylglycerol hydrolysis by lipoprotein lipase was studied. We found lipoprotein lipase to be inhibited by benzene boronic acid, with an apparent Ki of 8.9 micro M at pH 7.4. This indicates the presence of serine and histidine in the active site of the enzyme. Inhibition of lipoprotein lipase by benzene boronic acid is likely to be due to the formation of an inhibitor-enzyme complex having analogous bonding to the active site histidine and serine as the transition-state complex which precedes the formation of an obligatory acyl-enzyme intermediate. The presence of apolipoprotein C-II, the apolipoprotein activator of lipoprotein lipase, partly reverses the inhibition of lipoprotein lipase by benzene boronic acid. This reversal by apolipoprotein C-II has a distinct pH optimum in the range of 8-9.

Animals↗
PubMed1987

Aromatic boronic acids as probes of the catalytic site of human plasma lecithin-cholesterol acyltransferase.

We have recently proposed a catalytic mechanism for human plasma lecithin-cholesterol acyltransferase (EC 2.3.1.43) (J. Biol. Chem. (1986) 261, 7032-7043), implicating single serine and histidine residues in phosphatidylcholine cleavage and two cysteine residues in cholesterol esterification. We now confirm the involvement of serine and histidine in catalysing the phospholipase A2 action of lecithin-cholesterol acyltransferase by demonstrating the inhibition of this activity by phenylboronic acid (Ki = 1.23 mM) and m-aminophenylboronic acid (Ki = 2.32 mM), inhibitors of known serine/histidine hydrolases. The specificity of the interaction of aromatic boronic acids with catalytic serine and histidine residues and the putative formation of a tetrahedral adduct between boron and the lecithin-cholesterol acyltransferase serine hydroxyl group which is similar to the transition-state intermediate formed between phosphatidylcholine and the catalytic serine residue was suggested by: substrate protection against inhibition by phenylboronic acids; a much reduced incorporation of phenylmethane[35S]sulphonyl fluoride into the enzyme in the presence of phenylboronic acid; the lack of interaction of histidine- or serine-modified enzyme with immobilized phenylboronic acid in the presence of glycerol (Ve/Vo = 2.7 and 2.3 respectively) when compared to the native enzyme (Ve/Vo = 5.25). Fatty acyl-lecithin-cholesterol acyltransferase, produced by incubation of the enzyme with a lecithin-apolipoprotein A-I proteoliposome substrate, was not retarded upon the sorbent column (Ve/Vo = 1.5). Modification of the enzyme's two free cysteine residues with 5,5'-dithiobis(2-nitrobenzoic acid) or potassium ferricyanide reduced (Ve/Vo = 3.5) but did not abolish retardation on the sorbent column, indicating that these modifications resulted in steric hinderance of the interaction of the boron atom with the lecithin-cholesterol acyltransferase serine hydroxyl group. These data suggest that the serine and histidine residues are proximal within the enzyme catalytic site and that both cysteine thiol groups are close to the serine hydroxyl group. The presence of significant amino-acid sequence homologies between lecithin-cholesterol acyltransferase, triacylglycerol lipases and the transacylases of fatty acid synthase is also reported.

Binding Sites↗