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)

Whole and nonadherent Peyer's patch cells were shown to present antigen to cloned antigen specific T-cells, albeit less efficiently than spleen cells. Unlike spleen cells, adherent PP cells did not present antigen, and PP lacked cells with classical dendritic morphology. The antigen presenting and MLR-stimulating cell in both spleen and PP were concentrated in the low density (BPA floaters) population. Soluble antigens (OVA, HGG, HSA, and KLH) are poorly presented by PP and do not elicit a T-cell proliferative response in PP when fed orally. These antigens induce oral tolerance and Ts cells in PP, MLN, and spleen. As with systemic tolerance, however, Ts (as measured by adoptive transfer) are not necessary for the induction of tolerance and can be eliminated by colchicine and Cytoxan without a significant effect on the initiation of tolerance. Evidence from studies in various inbred strains of mice suggests that oral tolerance is dependent on genetic factors, but the susceptibility of the strain is different from that induced by the systemic injection of the same antigen. Data are also presented that suggest that in studies of oral tolerance to various antigens, care must be exercised in excluding the effect of diet.
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PMID:Oral tolerance and accessory-cell function of Peyer's patches. 619 10

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

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

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

The effective treatment depth in boron neutron capture therapy with thermal neutrons depends on the beam aperture, heavy water concentration, boron concentrations in the tumor, normal tissue and blood, tolerance dose to normal tissue and the capillary dose modification factor. In this study a 15 cm aperture is used and the tolerance dose to normal tissue is evaluated to be 15 Gy. Human pharmacokinetic data are evaluated for BSH and D, L-BPA, the two compounds currently used in thermal BNCT. Results show that the average measured tumor to blood boron ratios and standard deviations are 1.4 (0.4) for BSH and 4.3 (1.8) for subcutaneous melanoma. Experimental dose-depth phantom results for the Musashi Institute of Technology reactor are used with expected boron concentrations to calculate the maximum therapeutic depth in the brain for a thermal neutron beam. For BPA, the subcutaneous melanoma boron concentrations are assumed for intracranial metastases, and no allowance is made for possible enhanced uptake in the dopamine and noradrenaline tracts. Results for BSH are enhanced by inclusion of the capillary dose reduction factor. Calculations show that for expected boron tumor to blood ratios, the modified advantage depth is about 4 cm and the maximum therapeutic depth is about 1.5 cm for both BSH and BPA. Typical heavy water ratios of 15% increase the treatment depth by 0.5 cm, but this is offset by the use of smaller beam aperture in practice.
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PMID:Maximum therapeutic depth in thermal neutron capture therapy. 843 38

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

Large animal studies have been utilized to define tolerance of normal brain to irradiation and verify treatment planning programs with two recently installed epithermal neutron beams. The normal brain tolerance studies utilized two biological endpoints, magnetic resonance visible damage only and neurologic signs progressing to death. The studies focused on defining the proton RBE for the contaminant fast neutrons, and from nitrogen capture of thermal neutrons and boron capture reaction biologic effect. The proton RBE was approximately 3.0 to 6.7, depending on whether a dose reduction factor for the low gamma dose rate was employed. The microscopic distribution of the boron compounds, coupled with the extremely short length of the fission fragments from thermal neutron capture by 10B yields an observed biologic effect much less than would be expected from such high LET irradiation. This observed biologic effect, which is a product of the microdistribution of the boron atom and the relative biologic effect of the fission fragments has been termed compound factor. The compound factor was based on the calculated physical dose from the fission fragment in blood based on measured blood 10B concentration. The approximate compound factor for BSH was studied at the two institutions and it ranged from 0.27 to 0.55, depending on the site and the endpoint chosen. The mean compound factor for BPA was only studied at one site and was found to be 1.1 for both endpoints. The increase in the compound factor for BPA is in keeping with previous calculations based on the differences in compound distribution. Results of these studies has helped the initiation of phase I and phase II clinical trials at Brook haven National Laboratory and the planned European clinical trials at Petten, The Netherlands.
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PMID:A review: CNS effects and normal tissue tolerance in dogs. 915 Dec 25

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

C57BL mice bearing EL4 tumors and C3H / He mice bearing SCC VII tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days via implanted mini-osmotic pumps to label all proliferating (P) cells. Three hours after oral administration of l-p-boronophenylalanine-(10)B (BPA), or 30 min after intraperitoneal injection of sodium borocaptate-(10)B (BSH) or l-p-boronophenylalaninol (BPA-ol), a newly developed (10)B-containing alpha-amino alcohol, the tumors were irradiated with thermal neutron beams. For the combination with mild temperature hyperthermia (MTH) and / or tirapazamine (TPZ), the tumors were heated at 40 degrees C for 30 min immediately before neutron exposure, and TPZ was intraperitoneally injected 30 min before irradiation. The tumors were then excised, minced and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling ( = quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. Meanwhile, 6 h after irradiation, tumor cell suspensions obtained in the same manner were used for determining the apoptosis frequency in Q cells. The MN and apoptosis frequency in total (P + Q) tumor cells were determined from tumors that were not pretreated with BrdU. Without TPZ or MTH, BPA-ol increased both frequencies most markedly, especially for total cells. However, as with BPA, the sensitivity difference between total and Q cells was much larger than with BSH. On combined treatment with both MTH and TPZ, this sensitivity difference was markedly reduced, similarly to when BPA was used. MTH increased the (10)B uptake of all (10)B-compounds into both tumor cells. BPA-ol has good potential as a (10)B-carrier in neutron capture therapy, especially when combined with both MTH and TPZ.
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PMID:Evaluation of the potential of p-boronophenylalaninol as a boron carrier in boron neutron capture therapy, referring to the effect on intratumor quiescent cells. 1157 69

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


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