Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0393754 (HSA)
 2,996 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mercaptoundecahydrododecaborate (BSH) is an important agent for the boron neutron-capture therapy (BNCT). A sensitive high-performance liquid chromatographic (HPLC) method was developed for measuring BSH concentrations in rat tissues. Various tissue samples containing the drug were homogenized in a 1:1 (g/ml) mixture with phosphate buffered saline. The samples were then deproteinised with 4 volumes of acetonitrile and centrifuged. An aliquot of the supernatant was dried and reconstituted in 200 microliter of Tris-HC1 buffer. The samples were subjected to precolumn derivatization using the thiol reactive monobromobimane (mBB). The drug-mBB adduct was resolved by isocratic elution from a C18 reversed-phase column. The optimized mobile phase was methanol-0.02 M phosphate buffer (43:57, v/v) containing 0.01 M tetrabutylammonium dihydrogen phosphate as the ion-pairing agent with the final pH adjusted to 7.0. The flow-rate was set at 2.0 ml/min. The adduct was monitored by UV absorption at 373 nm. The analysis was completed in less than 15 min. The detection limit was 0.5 microgram/ml (0.25 microgram of boron). The assay method was linear over a concentration range of 0.5 to 50 micrograms/ml. This assay method could be used to evaluate the BSH concentrations in different tissues in studies on the targeted delivery of BSH.
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PMID:High-performance liquid chromatographic assay for sodium mercaptoundecahydrododecaborate in rat tissues. 779 87

A simple and rapid method for the quantitative measurement of mercaptoundecahydrododecarborate (BSH), (which presently is one of the most useful agents for Boron Neutron Capture Therapy) in human plasma was developed by using Fourier transform infrared spectroscopy. Different spacer thicknesses of the liquid sampling cell were examined and the optimal results were obtained by the 0.05 mm spacer. The subtraction of water absorbance from sample spectra resolved a B-H band at 2493 cm-1. The quantitative measurement of BSH was carried out by integration of the B-H band in the wavenumber range of 2534-2440 cm-1. However, at the lower BSH concentration range, a visual inspection of the spectrum to determine the wavenumber range was necessary so as to avoid any negative areas to be integrated. The lower limit of detection of BSH in aqueous solution and human plasma was 5 micrograms ml-1 (about 2.5 ppm of boron).
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PMID:FT-IR measurement of mercaptoundecahydrododecaborate in human plasma. 780 57

The response of the central nervous system to boron neutron capture irradiation, with either p-boronophenylalanine (BPA) or borocaptate sodium (BSH) as neutron capture agents, has been assessed using a rat spinal cord model. The mean latency times for the development of myelopathy after irradiation with the thermal neutron beam-alone, or in combination with BPA or BSH, were 23.7 +/- 0.3, 21.8 +/- 0.4 and 19.6 +/- 0.4 weeks, respectively. The radiation-induced lesion in the spinal cord was characterised by white matter necrosis. Due to the variations in the microdistribution of different neutron capture agents in body tissues, it was considered inappropriate to define the biological effectiveness of the high LET radiation, resulting from the 10B(n, alpha)7Li neutron capture reaction, relative to photon radiation, using the term 'relative biological effectiveness' (RBE). The term 'compound biological effectiveness' (CBE) factor was used as an alternative. ED50 values for the various irradiation modalities were calculated from probit fitted dose effect curves. Expressed as total physical absorbed doses these values were 13.6 +/- 0.4, 30.3 +/- 2.7 and 13.8 +/- 0.5 Gy after irradiation with the thermal neutron beam alone, or the thermal neutron beam in combination with BSH or BPA, respectively. The RBE of the thermal neutron beam was 1.4 +/- 0.04. The microdistribution of the two neutron capture agents played a crucial role in the determination of the overall biological effect, after thermal neutron activation. BSH, which is excluded from the CNS parenchyma by the blood brain barrier, had a low CBE factor value of 0.46 +/- 0.5. BPA, on the other hand, which crosses the blood brain barrier and distributes in the CNS parenchyma, had a higher CBE factor value of 1.33 +/- 0.16.
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PMID:Response of the central nervous system to boron neutron capture irradiation: evaluation using rat spinal cord model. 781 43

A high-performance liquid chromatographic (HPLC) method was developed for the determination of disodium mercaptoundecahydrododecaborate (BSH) in biological fluids. Monobromobimane was used as a precolumn derivatizing agent. A stable derivative was obtained. The derivative was separated on a C18 column using reversed-phase ion-pairing chromatography and detected by a spectrophotometric detector at 373 nm. The detection limit was 200 ng/ml (0.1 ppm boron). Calibration curves were prepared for rat urine and plasma samples. The calibration curves were linear in the range of 1 microgram/ml to 100 micrograms/ml for urine samples and 0.2 micrograms/ml to 50 micrograms/ml for plasma samples.
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PMID:Liquid chromatographic determination of sodium mercaptoundecahydrododecaborate in rat urine and plasma after precolumn derivatization. 786 25

The effects of boron neutron capture irradiation employing either BPA or BSH as neutron capture agents has been assessed using the dorsal skin of Fischer 344 rats. Pharmacokinetic studies, using prompt gamma spectrometry, revealed comparable levels of boron-10 (10B) in blood and skin after the intravenous infusion of BSH (100 mg/kg body wt.). The 10B content of blood (12.0 +/- 0.5 micrograms/g) was slightly higher than that of skin (10.0 +/- 0.5 micrograms/g) after oral dosing with BPA. Biphasic skin reactions were observed after irradiation with the thermal neutron beam alone or in combination with BPA or BSH. The time of onset of the first phase of the skin reaction, moist desquamation, was approximately 2 weeks. The time at which the second-wave skin reaction, dermal necrosis, became evident was dose-related and occurred after a latent interval of > or = 24 weeks, well after the acute epithelial reaction had healed. The incidence of both phases of skin damage was also dose-related. The radiation doses required to produce skin damage in 50% of skin sites (ED50 values) were calculated from dose-effect curves and these values were used to determine relative biological effectiveness (RBE) and compound biological effectiveness (CBE) factors for both moist desquamation and dermal necrosis. It was concluded on the basis of these calculations that the microdistribution of the two neutron capture agents had a critical bearing on the overall biological effect after thermal neutron activation. BSH, which was possibly excluded from the cytoplasm of epidermal cells, had a low CBE factor value (0.56 +/- 0.06) while BPA, which may be selectively accumulated in epidermal cells had a very high CBE factor (3.74 +/- 0.7). For the dermal reaction, where vascular endothelial cells represent the likely target cell population, the CBE factor values were comparable, at 0.73 +/- 0.42 and 0.86 +/- 0.08 for BPA ad BSH, respectively.
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PMID:Response of rat skin to boron neutron capture therapy with p-boronophenylalanine or borocaptate sodium. 797 8

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10, is irradiated with low energy (0.025 eV) thermal neutrons (nth) to yield alpha (4He) particles and 7Li nuclei (10B+nth-->[11B]-->4He + 7Li + 2.79 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of 10B and nth to individual cancer cells to sustain a lethal 10B(n, alpha) 7Li reaction. Boron delivery agents include a variety of compounds, such as the sulfhydryl containing polyhedral borane sodium borocaptate (Na2B12H11SH, [BSH]), boronoporphyrins, boronophenylalanine, carboranyl uridines (CBU), and boronated monoclonal antibodies (MAb). The present review will focus on three delivery systems that currently are under investigation in our laboratories, boronated monoclonal antibodies, carboranyl uridines, and boronophenylalanine. Methodology has been developed to heavily boronate MAb using a precision macromolecule, a "starburst" dendrimer, which can be linked to MAb by means of heterobifunctional reagents. Although the resulting immunoconjugates retain their in vitro immunoreactivity, they lose their in vivo tumor localizing properties and accumulate in the liver. In order to obviate this problem, work is now in progress to produce bispecific MAb, which can simultaneously recognize a tumor-associated antigen and a boronated macromolecule. Boron containing nucleosides are potential vehicles for incorporating boron compounds into nucleic acids of neoplastic cells. For this purpose, carboranyl uridines have been synthesized with the boron moiety on either the pyrimidine base or on the carbohydrate component. Although such structures appear to be avidly taken up and retained by tumor cells in vitro, only the 5-carboranyl-nucleosides are converted biologically to the nucleotide. There is no evidence, however, that the latter are incorporated into nucleic acids. Other carboranyl nucleosides currently are being synthesized that may have better tumor localizing properties. The potential use of boronophenylalanine as a capture agent for the treatment of melanoma metastatic to the brain also is under investigation. A nude rat model has been developed using human melanoma cells that are stereotactically implanted into the brain. BNCT-treated animals have either had prolonged survival times or continue to live compared to control rats that invariably died of their tumors, thereby suggesting therapeutic efficacy.
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PMID:Boron neutron capture therapy of primary and metastatic brain tumors. 808 33

Blood pharmacokinetics and tissue distribution of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a boron carrier with postulated melanin-seeking properties for boron neutron capture therapy, were determined in C57/BL mice with subcutaneous pigmented or non-pigmented B16 melanomas. Borocaptate sodium (BSH) was used as a boron compound without melanin-seeking properties in a comparative biodistribution study in the same animal tumour models. Administration of single doses showed that BPTU was retained better in the pigmented B16 tumour than in the non-pigmented variant. BPTU was found in large concentrations in kidney and liver. Brain boron was approximately 10-fold lower than tumour boron. On a molar basis, BPTU demonstrated higher affinity for B16 tumours than BSH. Owing to solubility limits, tumour boron concentrations in this mouse study were too low for effective application of BNCT. However, the high tumour-to-blood and tumour-to-normal tissues ratios indicate that, with appropriate formulation, BPTU could be a promising candidate for clinical BNCT.
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PMID:Pharmacokinetics in melanoma-bearing mice of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a candidate compound for boron neutron capture therapy. 814 52

The toxicity and binding of the three new carborane based compounds: 2 (1,2-dicarba-closo-dodecaborane (12)-1(-yl-methoxy)-2-(3-amino-propyl))-1,3-propanediol, called DAC-1; 7-(3-amino-propyl)-7,8-dicarba-nido-undecarborate (-1) called ANC-1; and rac-1-(9-o-carboranyl)-nonyl-2-methyl-glycero-3- phosphocholine, called B-Et-11-OMe, were analyzed with cultured human glioma cells, U-343MGa, and mouse melanoma cells, B16, as biological models. The previously developed compound di-sodium undecahydro-mercapto-closo-dodecarborate (BSH), which is tested for therapy of malignant gliomas, was analyzed for comparison. In the toxicity tests the cells were exposed to the substances at cell culture medium concentrations in the range 0-50 ppm boron for 1 or 20 h and thereafter analyzed regarding growth. Growth-disturbing effects were seen for the two compounds DAC-1 and B-Et-11-OMe at the concentrations corresponding to 15 and 50 ppm boron, respectively. The compounds ANC-1 and BSH showed no growth-disturbing effects at the tested concentrations. In the binding tests, the cells were incubated for 20 h at about the highest compound concentrations that did not cause growth disturbances. The boron content in the cells was then determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES) and in some cases ICP-mass spectrometry (ICP-MS). The most extensive binding was seen for DAC-1 and B-Et-11-OMe, which accumulated boron to about 100 and 60 times, respectively, compared with the concentration in the culture medium. The compound ANC-1 also accumulated boron in the cells but the boron could be easily washed out indicating no or only a weak binding. BSH did not accumulate. Further analysis should be made regarding biological properties such as intracellular compartmentalization, metabolic interference and tumor specificity of the compounds DAC-1 and B-Et-11-OMe.
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PMID:New carborane-based compounds for boron neutron capture therapy: binding and toxicity of ANC-1, DAC-1 and B-Et-11-OMe in cultured human glioma and mouse melanoma cells. 818 29

The radiobiological and clinical data concerning the alteration of the blood-brain barrier (BBB) after cerebral irradiation are reviewed. Several boron neutron capture therapy (BNCT) programs are at present under study in Europe and in the USA. In these programs, irradiation is considered to be delivered in several fractions, and one could also imagine, in principle, delivering BNCT after a full course of external radiotherapy of the brain. These options raise the question of the alteration of the normal BBB by previous irradiation. Before starting clinical applications, it then becomes necessary to assess the integrity of the BBB after different dose ranges and fractionation schemes, and after different time intervals following irradiation. Extrapolation of the available radiobiological and clinical data suggests that for rather small hydrophilic compounds, such as BSH or L-BPA, an early increase in transport through the BBB may be foreseen after single photon dose larger than 10 Gy or after a full standard radiotherapy regimen. However, there is no evidence that the first fractions of a BNCT application (typically 2 to 4 Gy equivalent per fraction) would increase the permeability of the BBB sufficiently to permit transport of large boronated compounds such as porphyrins or antibodies, or even of smaller hydrophilic compounds such as BSH and L-BPA. It can be concluded that the dose selectivity of BNCT is unlikely to be compromised by early alteration of the BBB due to the first fractions of a typical BNCT fractionated regimen.
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PMID:Alteration of the blood-brain barrier after irradiation: implication in boron neutron capture therapy. 821 73

Smallpox eradication culminated the most successful antimicrobial campaign in medical history. To characterize further the linear double-stranded DNA genome of the aetiological agent of smallpox, we have determined the entire nucleotide sequence of the highly virulent variola major virus, strain Bangladesh-1975 (VAR-BSH; 186,102 base pairs, 33.7% G + C; Genbank accession number, L22579). Here we highlight features of the molecule and focus on a few of the 187 putative proteins that probably contribute to pathogenicity and virus host-range properties. One hundred and fifty proteins were markedly similar to those of vaccinia virus (smallpox vaccine), for which a complete sequence has been reported for strain Copenhagen (VAC-CPN; 191,636 base pairs, 33.3% G + C). The remaining 37 proteins reflected variola-specific sequences or open reading frame divergences for variant proteins, which are often truncated or elongated compared with their vaccinia counterparts.
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PMID:Potential virulence determinants in terminal regions of variola smallpox virus genome. 826 86


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