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)

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.
Cancer Invest 1996
PMID:Boron neutron capture therapy of brain tumors: past history, current status, and future potential. 895 58

Five hybridomas producing human monoclonal antibodies (MAbs) of IgA and IgM isotypes reacting with the tumour associated TF antigen were generated after in vitro immunisation or antigen specific isolation of normal peripheral blood B cells using asialoglycophorin, a TF containing antigen. All 5 antibodies produced by the hybridomas bound strongly to asialoglycophorin and to synthetic glycoprotein containing the TF-epitope, with preference to the beta form (Galb1-3GalNAc-beta-O-CETE-BSA) as compared to the alpha form (Galbl-3GalNAc-alpha-O-APE-HSA) in ELISA. Flow cytometry analysis revealed binding to carcinoma cell lines of different origin such as breast, colon, pancreas, ovary, bladder, lung and, in addition, to some tumour cell lines of haematopoietic origin. Immunohistochemical analysis of tumour tissues revealed staining patterns typical for mucins, and the antibodies were found to bind to glycoproteins among the MUC-1 positive high m.w. fraction shed from a TF antigen positive ovarian carcinoma cell line.
Int J Cancer 1997 Jan 06
PMID:Human monoclonal antibodies specific for the tumour associated Thomsen-Friedenreich antigen. 898 92

T, Tn, and sialyated Tn (sTn) are pancarcinoma antigens, and increased expression of these carbohydrate epitopes has been correlated with a poor prognosis in several epithelial malignancies. Ten murine monoclonal antibodies have been generated to these antigens, and compared by ELISA and immunohistochemistry to established mAbs reactive with these antigens. Nine mAbs (3 IgM and 6 IgG) reactive with synthetic T-human serum albumin (T-HSA) were produced after immunizing BALB/c mice with a synthetic T-keyhole limpet hemocyanin glycoconjugate (T-KLH). An additional IgM mAb (145.22) was produced in mice immunized with erythrocytes isolated from a patient with Tn syndrome. Three IgM and six IgG1 mAbs reactive with T-HSA did not react with natural T antigen present on desialyated glycophorin. All three IgM and several IgG1 mAbs, however, did react with LS-174T, a mucinous colon carcinoma cell line, 647V, a human bladder carcinoma cell line, and TA3Ha, a murine mammary carcinoma cell line as well as fresh frozen colon carcinomas. MAb 145.22 reacted with both natural and synthetic sources of sTn and Tn, as well as with LS-174T cells and mucin deposits in 10/11 colon carcinomas on fresh-frozen sections. MAb B72.3 reacted strongly with ovine submaxillary mucin (OSM) and sTn-HSA, while mAb CC49, a second-generation mAb to TAG-72 carcinoma mucin, reacted strongly with OSM, less strongly with desialyated OSM, and only weakly with sTn-HSA, suggesting that the epitope specificity for mAb CC49 is distinct from that of B72.3.
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PMID:Specificity analysis of murine monoclonal antibodies reactive with Tn, sialylated Tn, T, and monosialylated (2-->6) T antigens. 898 50

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.
Cancer Res 1997 Mar 15
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

C3H/He mice bearing SCC VII tumours received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days via implanted mini-osmotic pumps, to label all proliferating (P) cells. 20 min after intraperitoneal injection of sodium borocaptate-10B (BSH), or 3 h after oral administration of dl-p-boronophenylalanine-10B (BPA), the tumours were irradiated with thermal neutrons. To modify the uptake dose of 10B, nicotinamide (NA) was intraperitoneally injected 60 min before the administration of 10B-compounds and/or the tumours were heated to 41.5 degrees C for 20 min immediately before irradiation. After irradiation, the tumours were excised, minced and trypsinized. The tumour cell suspensions were then incubated with cytochalasin-B (a cytokinesis-blocker). The micronucleus (MN) frequency in cells not BrdU-labelled (quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. With or without the administration of 10B-compounds, the sensitivity of Q cells was lower than that of total (P + Q) tumour cells. With thermal neutron irradiation in the presence of either BPA or BSH, the MN frequency in each cell population was increased. A greater increase in the MN frequency of total tumour cells was observed after thermal neutron irradiation in the presence of BPA than in the presence of BSH. The distribution of 10B from BPA into tumour cells was thought to be more dependent on the uptake ability of the tumour cells than that from BSH. Sufficient quantity of 10B from these two 10B-compounds to cause a highly lethal event inside the cancer cell with thermal neutron irradiation could not be delivered to Q cells. When NA and/or heat treatment were combined with 10B-compound administration, NA increased MN frequency in the BSH treated total cells, and heat treatment elevated MN frequency in Q cells. From the viewpoint of cell kill effect, the combined treatment with nicotinamide and heat treatment was more useful than treatment with either nicotinamide or heat treatment alone, not only in the total tumour cells but also in the Q cells.
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PMID:Modification of the response of a quiescent cell population within a murine solid tumour to boron neutron capture irradiation: studies with nicotinamide and hyperthermia. 916 76

In neutron capture therapy, whose effectiveness depends on the tumor distribution of neutron capture compound and the neutron energy distribution, controlling quiescent tumor cells with clonogenic potential is critical for therapeutic gain, as is the case in conventional radio- and chemotherapy. Tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating cells. After administration of sodium borocaptate-10B (BSH), dl-p-boronophenylalanine-10B (BPA) or gadodiamide hydrate (Omniscan), the tumors were irradiated with neutrons of different cadmium (Cd) ratio, and then isolated and incubated with cytochalasin-B (a cytokinesis blocker). The micronucleus (MN) frequency in cells without BrdU labeling (quiescent cells) was determined using immunofluorescence staining for BrdU, and that for total cells was obtained from tumors not pretreated with BrdU. Without drugs, quiescent cells showed lower MN frequencies than total cells, but neutron irradiation reduced gamma-ray sensitivity difference between the two. Relative biological effectiveness (RBE) of neutrons compared with gamma-rays was greater in quiescent cells than in total cells, and low Cd ratio neutrons tended to exhibit large RBE values. With neutron capture compounds, MN frequency for each cell population was increased, especially when high Cd ratio neutrons were used. BPA increased the MN frequency for total cells to a greater extent than BSH. However, the sensitivity of quiescent cells treated with BPA was lower than that in BSH-treated quiescent cells. This tendency was clearly observed in high Cd ratio neutrons. Omniscan only slightly increased the MN frequency in both cell populations, compared with irradiation alone, without drugs. From the viewpoint of increasing the quiescent cell sensitivity, tumors should be irradiated with high Cd ratio neutrons after BSH administration.
Jpn J Cancer Res 1998 Jan
PMID:Responses of total and quiescent cell populations in solid tumors to boron and gadolinium neutron capture reaction using neutrons with two different energy spectra. 951 Apr 80

Boron neutron capture therapy (BNCT) destroys tumor cells by means of alpha particles and recoil protons emitted by 10B(n, alpha)7Li reaction. For BNCT to be effective, the tumor/normal tissue concentration ratio of 10B must be larger than 1.0, because neutron distribution is not selective. We examined the combination of 10B-enriched borocaptate sodium (BSH) with flavone acetic acid (FAA) as a model compound which causes vascular collapse in squamous cell carcinoma in mice (SCCVII tumors) and would increase the tumor/normal tissue concentration ratio of 10B. FAA (200 mg/kg, i.p.) was injected, and 5 min later BSH (75 mg/kg, i.v.) was administered, followed 15 to 180 min later by irradiation with thermal neutrons. The 10B concentrations were measured by prompt gamma ray spectrometry. Without FAA, tumor 10B concentrations were less than or equal to normal tissue concentrations at all time intervals, except that the concentrations were 1.7- to 2.7-fold greater in tumor than muscle at 15 and 180 min after injection of BSH. With FAA, 10B concentrations 2.1- to 6.9-fold greater in tumor than in muscle were achieved at all intervals tested. For blood and skin, significant differential accumulations were found in tumors at 120 and 180 min. Tumor/liver ratios were less than 1 at all times. Cell survival was determined by in vivo/in vitro colony assay, and increasing radiosensitization correlated with increasing tumor 10B concentrations, whether or not they were achieved with FAA. Tumor control rates, determined at 180 days after BNCT, similarly appeared to depend only on 10B levels at the time of irradiation. Because 10B levels correlate with the radiation response of tissues, a therapeutic gain would be expected whenever the tumor levels exceed normal tissue levels, such as in tumors located in muscle irradiated at 15-180 min after FAA + BSH, or in those in skin irradiated at 120 and 180 min.
Jpn J Cancer Res 1998 Mar
PMID:Effects of boron neutron capture therapy using borocaptate sodium in combination with a tumor-selective vasoactive agent in mice. 960 Jan 29

SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating cells. After injection of tirapazamine (TPZ), a bioreductive agent, combined with sodium borocaptate-10B (BSH) or dl-p-boronophenylalanine-10B (BPA) administration, the tumors were irradiated with thermal neutrons, and then isolated and incubated with cytochalasin-B (a cytokinesis blocker). The micronucleus (MN) frequency in cells without BrdU labeling (quiescent (Q) cells) was determined by means of immunofluorescence staining for BrdU, and that for total cells was obtained from tumors not pretreated with BrdU. Even when no 10B-compound was administered, TPZ increased the MN frequency of tumor cells including Q cells, resulting in reduction of the difference in MN frequency between total and Q cells, mainly by increasing the MN frequency of Q cells. TPZ increased the MN frequency of Q cells when combined with BPA administration, but TPZ showed no apparent effect on each cell population when combined with BSH. Namely, TPZ reduced the difference in MN frequency between total and Q cells caused by 10B-compound administration, especially when BPA was administered. From the viewpoint of the overall cell killing effect in boron neutron capture therapy (BNCT), combination with TPZ appeared to be useful in BPA-BNCT, but not in BSH-BNCT.
Jpn J Cancer Res 1998 Jul
PMID:Applicability of combination with tirapazamine in boron neutron capture therapy. 973 84

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.
Cancer Lett 1998 Sep 11
PMID:Boron neutron capture therapy for glioblastoma: improvement of boron biodistribution by hyaluronidase. 983 25

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.
Jpn J Cancer Res 1998 Dec
PMID:Effect of electroporation on cell killing by boron neutron capture therapy using borocaptate sodium (10B-BSH). 1008 97


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