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Query: UMLS:C0393754 (HSA)
 2,996 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We postulated that nitroimidazoles, previously used for radiosensitizing solid tumors, may be interesting templates as carriers of 10B for boron neutron capture therapy. To test this hypothesis, we synthesized a 10B-enriched nitroimidazole, 1-2[(undecahydro-closo-dodecaborato)thio]ethyl]-2- methyl-5-nitroimidazole (imidocaptate), by coupling the Cs salt of BSH (Cs2-10B12H11SH) with 1-(2-bromoethyl)-2-methyl-5-nitroimidazole followed by purification of the adduct. Imidocaptate was taken up by V-79 cells in culture and showed no inherent toxicity under euoxic conditions up to 1.05 mM (126 micrograms of 10B/mL of culture medium). Imidocaptate showed a dose-dependent decrease in D0 when the treated cells were irradiated with a thermal neutron beam. At the highest dose tested (126 micrograms of 10B/mL of culture medium), the ratio of control to sample D0 values was 2.6 for both linear quadratic and single-hit multitarget models. At 33 micrograms of 10B/mL, imidocaptate showed a control/treated D0 ration (1.5) equal to that observed with the disulfide form of BSH at 28 micrograms of 10B/mL. Compared to BSH and its disulfide, the reduced toxicity and equipotency of imidocaptate suggest that this agent may be useful for boron neutron capture therapy of cancer.
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PMID:Synthesis and evaluation of a boronated nitroimidazole for boron neutron capture therapy. 869 85

A histopathological study was carried out on the spinal cord of rats after boron neutron capture (BNC) irradiation. Rats were irradiated with thermal neutrons alone or in combination with borocaptate sodium (BSH) or p-boronophenylalanine (BPA). Spinal cords were examined 1 year after irradiation, or at earlier times in rats developing myelopathy. Considered overall, the pathology of the spinal cord after BNC irradiation was comparable with that reported previously after X irradiation of the spinal cord in the identical strain of rat. When BSH was used as the neutron capture agent, the biologically effective dose of radiation delivered to the CNS parenchyma was a factor of -2.7 lower than that delivered to the vascular endothelium. In effect, the blood vessels were selectively irradiated using this BNC modality. The resultant pathology was similar to that observed after irradiation with thermal neutrons alone or in the presence of BPA, situations in which the CNS vasculature was not selectively irradiated. This points to the vascular endothelium as being the critical target cell population, damage to which results in the development of the lesions seen in the spinal cord after BNC irradiation and, by inference, after irradiation with more conventional modalities.
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PMID:Boron neutron capture irradiation of the rat spinal cord: histopathological evidence of a vascular-mediated pathogenesis. 875 10

The Fischer 344 rat spinal cord model has been used to evaluate the response of the central nervous system to boron neutron capture irradiation with variable doses of the neutron capture agent, borocaptate sodium (BSH). Three doses of BSH, 190, 140 and 80 mg/kg body weight, administered by i.p. injection, were used to establish the time course of 10B accumulation in and removal from the blood. After administration of the two lower doses of BSH, blood 10B levels peaked at 0.5 h after injection, with no significant (P > 0.1) change at 1 h after injection. Beyond this time point, levels of 10B in the blood began to decrease after a dose of 80 mg/kg BSH, but remained constant until 3 h after administration after the two higher doses of BSH. Myelopathy developed after latent intervals of 20.4 +/- 0.1, 20.8 +/- 1.4, 15.0 +/- 0.8, 15.4 +/- 0.4 and 15.6 +/- 0.4 weeks, following irradiation with thermal neutrons in combination with BSH at doses of 20, 40, 80, 140 and 190 mg/kg body weight, respectively. The radiation-induced lesion in the spinal cord was white matter necrosis. ED50 values for myelopathy were calculated from probit-fitted dose-effect curves. Expressed as total physical absorbed doses, these values were 20.7 +/- 1.9, 24.9 +/- 1.2, 27.2 +/- 0.9, 28.4 +/- 0.6 and 32.4 +/- 1.9 Gy after irradiation with thermal neutrons in the presence of 20, 40, 80, 140 and 190 mg/kg body weight of BSH, respectively. The compound biological effectiveness (CBE) factor values, estimated from this data, were in the range 0.49-0.55. There was no significant (P > 0.1) variation in the CBE factor for BSH as a function of increasing 10B concentration in the blood. It was concluded that there was no significant synergistic interaction between the low and high linear energy transfer (LET) components of the boron neutron capture (BNC) radiation field.
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PMID:Boron neutron capture irradiation of the rat spinal cord: effects of variable doses of borocaptate sodium. 878 2

Sodium mercaptoundecahydrododecaborate or BSH is a compound most widely used for boron neutron capture therapy (BNCT). Liposome formulations containing BSH, with or without steric stabilization, were prepared as potential agents for delivery of boron compounds for BNCT. Liposomes composed of DPPC/CHOL in a molar ratio 1:1 (PEG concentration: 5 mol%) were prepared having an average diameter in the range of 100-110 nm 200 mu L of liposomes (l.88 mg phospholipid/mouse and 3.5-5.8 mg BSH/kg body weight) were injected in mice via the tail vein. Both types of liposomes resulted in a significant improvement in the circulation time of BSH compared to that obtained previously after injecting free BSH. The mean percent injected BSH remaining in circulation at the end of 24 h was 19% for the PEG-liposomes compared to the corresponding value of 7% for the conventional liposomes. The mean percent uptake by the liver and spleen was not significantly different for the two types of liposomes; the blood/RES ratios were higher for the PEG-liposomes at all time points indicating that a higher fraction of injected BSH was available in circulation. The PEG-liposomes could be further explored as a means of enhance boron drug delivery to tumor cells for BNCT.
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PMID:Liposomal formulations containing sodium mercaptoundecahydrododecaborate (BSH) for boron neutron capture therapy. 886 Jun 83

A delivery molecule for directed boron neutron capture therapy against epidermal growth factor (EGF) receptor-rich tumors, such as gliomas, squamous carcinomas, and breast cancers, is presented. EGF and sulfhydryl boron hydride (BSH) were covalently coupled to an allylated 70 kDa dextran chain to form a conjugate. Conjugates with low and high substitution rates of BSH, as well as without BSH, were investigated. The conjugate with a low amount of boron had approximately 6 BSH (72 boron atoms) per dextran, while the conjugates with higher amounts had an average substitution of 55 BSH (660 boron atoms) per dextran. The maximum substitution of boron to dextran in a single experiment was over 800 boron atoms. Binding, retention, and internalization of 125I-labeled conjugates were investigated on cultured human glioma cells. Binding of the conjugates was EGF receptor specific, but the amount of BSH coupled to dextran affected specificity, more than the presence of dextran. The nonspecific binding of the conjugates increased with the amount of attached boron. This was partly due to nonspecific adhesion to the plastic in the culture dishes. [125I]EGF-allyldextran with 6 BSH had a binding maximum after 4 h of continuous incubation and thereafter decreased in binding, while [125I]EGF-allyldextran with the higher substitution rate had a slow increase of binding during 24 h. Over 93% of the radioactivity bound to the cells was internalized, but the retention was quite poor. Only one-third of the cell-bound activity was still associated to the cells 4 h after incubation had ended. In conclusion, it is possible to load the conjugates produced with high amounts of boron, and they retained specificity for the EGF receptor and internalized into cultured cells. Theoretical calculations show that about 10(3) boron atoms per EGF-based conjugate are needed to give a satisfactory therapeutic response. These conjugates are within reach of that level.
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PMID:Development and in vitro studies of epidermal growth factor-dextran conjugates for boron neutron capture therapy. 888 21

The short (< 10 microns) ranges of alpha and 7Li particles produced during boron neutron capture therapy (BNCT) make the partitioning of the boronated drug within and without the cell of critical importance. The evaluation of the potential usefulness of a boron-containing substance for BNCT requires information about its intracellular accumulation. In the present report, an in vitro method is described for direct measurement of intracellular boron based on rapid centrifugation of cells through a layer of mineral oil and silicon oil to strip away extracellular growth medium. The intracellular concentrations of boronophenylalanine (BPA), mercaptoborane (BSH) and horic acid in malignant cells and in normal cells have been compared. The accumulation ratio is defined as the ratio of the intracellular to the extracellular boron concentration. Boric acid showed an accumulation ratio of 1 while the ratios for BSH and BPA were dependent on cell type and tended to be greater for BPA than for BSH in malignant but not in normal cells.
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PMID:Accumulation of boron in malignant and normal cells incubated in vitro with boronophenylalanine, mercaptoborane or boric acid. 889 82

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

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield alpha particles and recoiling lithium-7 nuclei. High-grade astrocytomas, glioblastoma multiforme, and metastatic brain tumors constitute a major group of neoplasms for which there is no effective treatment. There is growing interest in using BNCT in combination with surgery to treat patients with primary, and possibly metastatic brain tumors. For BNCT to be successful, a large number of 10B atoms must be localized on or preferably within neoplastic cells, and a sufficient number of thermal neutrons must reach and be absorbed by the 10B atoms to sustain a lethal 10B(n, alpha)7 Li reaction. Two major questions will be addressed in this review. First, how can a large number of 10B atoms be delivered selectively to cancer cells? Second, how can a high fluence of neutrons be delivered to the tumor? Two boron compounds currently are being used clinically, sodium borocaptate (BSH) and boronophenylalanine (BPA), and a number of new delivery agents are under investigation, including boronated porphyrins, nucleosides, amino acids, polyamines, monoclonal and bispecific antibodies, liposomes, and epidermal growth factor. These will be discussed, and potential problems associated with their use as boron delivery agents will be considered. Nuclear reactors, currently, are the only source of neutrons for BNCT, and the fission process within the core produces a mixture of lower-energy thermal and epithermal neutrons, fast or high (> 10,000 eV) energy neutrons, and gamma rays. Although thermal neutron beams have been used clinically in Japan to treat patients with brain tumors and cutaneous melanomas, epithermal neutron beams should be more useful because of their superior tissue-penetrating properties. Beam sources and characteristics will be discussed in the context of current and future BNCT trials. Finally, the past and present clinical trials on BNCT for brain tumors will be reviewed and the future potential of BNCT will be assessed.
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PMID:Boron neutron capture therapy of brain tumors: past history, current status, and future potential. 895 58

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.
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PMID: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. 906 83

The response of the central nervous system (CNS) to fractionated doses of boron neutron capture (BNC) irradiation was assessed using a rat spinal cord model. The thermal neutron beam at the Brookhaven Medical Research Reactor (BMRR) was used for the spinal cord irradiations, with borocaptate sodium (BSH) as the neutron capture agent. Irradiations were given as a single dose or as two or four equal fractions. The ED50 for radiation-induced myeloparesis, as indicated by limb paralysis within 7 months, after a single exposure to thermal neutrons in the presence of BSH (blood boron-10 content approximately 70 micrograms/g) was 27.2 +/- 0.9 Gy. This was expressed as the total physical dose to the blood. Dividing the radiation dose into two consecutive daily fractions or four fractions given over 1 week, resulted in ED50 = 32.0 +/- 1.4 and 31.5 +/- 0.4 Gy respectively. Although there was no significant dose sparing in moving from two to four fractions, there was a dose increment of approximately 17% as compared with single-dose irradiation. The variation in the relative biological effectiveness of the thermal neutron beam, with dose per fraction, was established using data from a previous study with single and fractionated doses of thermal neutrons in the absence of a neutron capture agent. This varied from 1.40 to 3.74 for thermal neutron dose per fraction in the range 13.6-1.5 Gy. Previously published CBE factors for both BSH and BPA have been recalculated in the present report to take into account the change in the RBE of the thermal neutron beam with dose. In all cases the recalculated CBE factors were lower than those obtained previously. Values for this parameter increased with fraction number. In the case of BSH, the CBE factor increased from 0.36 +/- 0.03 after a single-dose to 0.51 +/- 0.06 after four fractions.
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PMID:Response of the central nervous system to fractionated boron neutron capture irradiation: studies with borocaptate sodium. 912 Mar 54


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