Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to utilize a well-established rat glioma to evaluate boron neutron capture therapy for the treatment of malignant brain tumors. Boron-10 (10B) is a stable isotope which, when irradiated with thermal neutrons, produces a capture reaction yielding high linear energy transfer particles (10B + 1nth----[11B]----4He(alpha) + 7Li + 2.79 MeV). The F98 tumor is an anaplastic glioma of CD Fischer rat origin with an aggressive biological behavior similar to that of human glioblastoma multiforme. F98 cells were implanted intracerebrally into the caudate nuclei of Fischer rats. Seven to 12 days later the boron-10-enriched polyhedral borane, Na2B12H11SH, was administered intravenously at a dose of 50 mg/kg body weight at varying time intervals ranging from 3 to 23.5 hours before neutron irradiation. Pharmacokinetic studies revealed blood 10B values ranging from 0.33 to 10.5 micrograms/ml depending upon the time after administration, a T1/2 of 6.2 hours, normal brain 10B concentrations of 0.5 microgram/g, and tumor values ranging from 1.1 to 12.8 micrograms/g. No therapeutic gain was seen if the capture agent was given at 3 or 6 hours before irradiation with 4 x 10(12) n/cm2 (10 MW-min; 429 cGy). A 13.5-hour preirradiation interval resulted in a mean survival of 37.8 days (P less than 0.01), compared to 30.5 days (P less than 0.03) for irradiated controls and 22.1 days for untreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Boron neutron capture therapy of a rat glioma. 229 79

A tetraphenylporphyrin bearing four dicarbollide ([B9C2H11]-) cages linked to the o-phenyl ring positions by anilide bonds, known as boronated tetraphenylporphyrin (BTPP), has been synthesized in excellent yield from tetra-(o-aminophenyl) porphyrin and carborane carbonyl chloride followed by base-assisted cage opening and ion exchange to give the highly water-soluble potassium salt. Preliminary studies showed that BTPP accumulates in liver and in a syngeneic ovarian carcinoma, but not in normal brain parenchyma, of mice infused with BTPP subcutaneously for 6 or 7 days via surgically implanted osmotic minipumps. In this study, the uptake of boron was measured in human gliomas xenografted subcutaneously to athymic nude mice in which BTPP was infused intraperitoneally or subcutaneously or both for 3 or 7 days by using similar minipumps. Immunocompetent mice bearing a syngeneic ovarian carcinoma were similarly infused to provide comparative data. Bulk concentrations of boron up to 18 micrograms/g of glioma and up to 45 micrograms/g of carcinoma were observed when up to 102 micrograms/g of tissue was present in the liver after 7 days of BTPP infusion. Glioma boron concentrations were increased by approximately 80% on the average (up to 33 micrograms/g) when correspondingly greater amounts of BTPP were infused in only 3 days. Cell counts and chemical tests on blood samples from individual mice indicate that BTPP causes moderate hepatotoxicity and thrombocytopenia. This hepatohematic toxicity syndrome should be taken into account if BTPP or a similar agent is used for boron neutron-capture therapy (BNCT) of human malignancies.
 ...
PMID:Uptake of a nido-carboranylporphyrin by human glioma xenografts in athymic nude mice and by syngeneic ovarian carcinomas in immunocompetent mice. 240 7

A CD 344 rat glioma model currently used to investigate boron neutron capture therapy (BNCT) was used to demonstrate an increased survival rate after thermal neutron irradiation enhanced by administration of 10B-enriched polyhedral borane, Na2B12H11SH. To investigate the possible effects of BNCT on normal and tumor microvasculature, we subjected animals to sublethal neutron irradiation with and without intravenous injection of 50 mg/kg of enriched 10B and performed histological and ultrastructural analyses. In the rats that did not undergo tumor transplantation, minimal detectable morphological changes in the microvasculature of the central nervous system were observed after treatment, both in the immediate posttreatment phase and at 10 months. Light microscopy of cerebral cortex and caudate nucleus showed normal cytoarchitecture with no evidence of vessel occlusion, hyalinization, thickening, or reactive gliosis. Electron microscopy demonstrated that the junctional complexes of the endothelial cells, the basal lamina, and the perivascular glia were comparable in both treated and control animals. In those animals examined at 18 months, pathological membrane-bound clusters of electron-dense vesicles were seen in pericytes. In the rats implanted with gliomas, vascular proliferation with evidence of breakdown of the blood-brain barrier and vasogenic edema occurred. In the irradiated animals, we noted increased peritumoral edema 3 days after treatment. At seven days, both increased peritumoral edema and necrosis were noted in the rats treated with BNCT. These observations show that the normal microvasculature of the central nervous system tolerates BNCT at the treatment parameters used in our experimental model; the progressive edema and necrosis found in the peritumoral region after BNCT indicate a pathological endothelial response.
 ...
PMID:Ultrastructural microvascular response to boron neutron capture therapy in an experimental model. 271 78

The vasculature and capillary permeability of gliomas induced by ethylnitrosourea in Sprague-Dawley rats were studied with horseradish peroxidase and Evans blue dye. The distribution of the boron-10 compound, Na2(10)B12H11SH, which is now in clinical use for boron neutron capture therapy (BNCT) for brain tumors, was investigated quantitatively using neutron-induced alpha-autoradiography. The vasculature and the degree of capillary permeability varied widely, depending mainly on the size of the glioma, and were often heterogeneous even in the same tumor. The distribution of boron-10 also varied, correlating to capillary permeability. The boron-10 concentration and the tumor:blood concentration ratio in large and medium-sized gliomas were adequate for successful BNCT. This study suggests that the vasculature and capillary permeability of the target brain tumor exert an important influence on the therapeutic efficacy of BNCT.
 ...
PMID:Capillary permeability and boron distribution in ethylnitrosourea-induced rat glioma. 334 84

The biodistribution of boron sulfhydryl (BSH) was evaluated for boron neutron capture therapy of brain tumors. A selective boron delivery to the neoplasm is a prerequisite for successful therapy. The uptake of BSH after intravenous administration was analyzed in neoplastic and normal tissues in 61 patients undergoing craniotomies for intracranial tumors. The patients received 10 to 100 mg of BSH/kg (5-50 mg of 10B/kg) body weight, 2 to 72 hours before surgery. The tumor boron concentrations ranged from 0.2 ppm (micrograms/g) in a low-grade glioma to 19.5 ppm in a high-grade glioma. The tumor to blood boron ratio rose above 1 in 15 of 24 high-grade intracerebral tumors, 18 h or more after BSH infusion. The boron concentration in high-grade tumors was heterogeneous. Low-grade intracerebral tumors showed a low boron concentration with a tumor to blood ratio below 1. Extracerebral tumors, mainly meningiomas, showed boron concentrations comparable with high-grade tumors, with a tumor to blood ratio above 1 in 10 of 17 patients. The boron concentrations in skin and muscle compared roughly with the blood values. Boron did not enter normal brain in any significant amount. In high-grade tumors, tumor to brain ratios were above 2. Low boron concentrations in normal brain make BSH safe for a Phase I normal tissue tolerance study. Computed tomographic contrast enhancement was evaluated to tumor boron uptake for 30 patients. Tumor enhancement on computed tomography does not permit the prediction of individual tumor boron concentrations; however, the absence of a contrast enhancement was always associated with low boron uptake.
 ...
PMID:Biodistribution of boron sulfhydryl for boron neutron capture therapy in patients with intracranial tumors. 773 8

Boron neutron capture therapy is a treatment modality for cancer that depends on the specific uptake of boron by the tumor cells. The infiltrative growth of malignant gliomas requires that boron reach and accumulate in migrating cells outside the margin of the tumor; thus, it is important that the biodistribution of new boron compounds is also studied in the surrounding healthy brain tissue. This study is undertaken in the present work, in which the biodistribution and pharmacokinetics of sulfhydryl boron hydride (BSH) and boronated porphyrin (BOPP) in the RG2 rat glioma model are investigated. This model mimics the characteristics of human glioma with cells migrating into the surrounding brain. The animals were infused intravenously with either BSH (25 micrograms or 175 micrograms of boron per gram of body weight) or BOPP (12 micrograms of boron per gram body weight). For the low dose of BSH, the maximum tumor-boron content was 8 ppm at approximately 9 hours after the infusion with a tumor-to-blood ratio of 0.6. At the higher dose, the corresponding figures were 15 ppm after 12 hours with a tumor-to-blood ratio of 0.5. For BOPP, a tumor-boron concentration of 81 ppm was achieved 24 hours after the infusion and sustained in that range for at least 72 hours. The tumor-to-blood ratio at 24 hours was slightly above 6, but continued to increase as the blood was cleared. These results indicate that both compounds are spread into the normal brain tissue following the same pathways as the migrating tumor cells and in this way can be taken up even in distant tumor cell foci.
 ...
PMID:A comparative study on the pharmacokinetics and biodistribution of boronated porphyrin (BOPP) and sulfhydryl boron hydride (BSH) in the RG2 rat glioma model. 778 56

Low-density lipoprotein (LDL) uptake in gliomas was studied to find out if LDL has potential as a drug carrier of boron, especially for boron neutron capture therapy. Single photon emission tomography (SPET) was performed 2 h and 20 h after intravenous injection of autologous 99mTc-labelled LDL in four patients with untreated and five patients with recurrent glioma. 99mTc-LDL uptake was compared with the uptake of 99mTc-labelled human serum albumin (HSA), an established blood pool marker. The intra- and peritumoral distributions of radioactivity in the SPET images were not identical for radiolabelled LDL and HSA. The mean LDL tumour to brain ratio, determined from transversal SPET slices at 20 h post injection, was 1.5 in untreated and 2.2 in recurrent gliomas; the corresponding ratios for HSA were 1.6 and 3.4. The brain to blood ratio remained constant at 2 h and 20 h in both types of tumours. These data are not consistent with highly selective, homogeneous uptake of LDL in gliomas. However, the different tumoral distribution and rate of uptake of 99mTc-LDL, as compared with 99mTc-HSA, indicate that the uptake of LDL is different from that of HSA and that further studies on the mechanism of LDL uptake in glioma are warranted.
 ...
PMID:Accumulation of 99mTc-low-density lipoprotein in human malignant glioma. 784 Oct 57

Because of the short range of the highly energetic particles helium-4 and lithium-7 that results from neutron-induced disintegration of boron-10, the efficacy of Boron Neutron Capture Therapy (BNCT) is heavily dependent on 10B-microlocation. Despite the crucial importance of boron-10, there is little specific information with regard to the agent currently used for inducing BNCT, namely Na2B12H11SH. In the present study, a subcellular 10B-location was investigated in tumor tissue obtained from seven patients with glioblastoma World Health Organization Grade IV. These patients received Na2B12H11SH at doses used in therapeutic trials (75 mg/kg body weight in five patients, and 150 mg/kg body weight in two patients, respectively). In three cases, boron-10 was identified in glioblastoma cells by laser microprobe mass analysis. In these tumors, boron-10 was found only in the nuclei of neoplastic cells but not in other cell compartments. These preliminary results suggest a predominant association of Na2B12H11SH with the nuclei of malignant glioma cells and thus support the value of Na2B12H11SH as a suitable boron carrier for BNCT.
 ...
PMID:Subcellular boron-10 localization in glioblastoma for boron neutron capture therapy with Na2B12H11SH. 793 21

A well-characterized in vitro cryogenic preparation for ion microscopic isotope imaging, which minimizes redistribution of diffusible species, was used to determine the distribution of boron in GS-9L gliosarcoma cells incubated with the boron neutron capture therapy agent, p-boronophenylalanine (BPA). At the subcellular level, boron from BPA distributes relatively homogeneously within the glioma cell. Boron from BPA was eliminated rapidly, indicating that most is unbound. Thus a large pool of boron is susceptible to diffusion artifact. Removal of this artifact increases the degree of confidence in microdosimetric results inferred from the homogeneous subcellular distribution. The ion microscopic imaging of boron in subcutaneous tumors cryofixed in situ was achieved in rats treated with BPA. Boron signals from BPA were adequate to image microdistributions at the 1-micron resolution level. As in the in vitro case, boron did not localize discretely at the subcellular level. However, boron heterogeneity was seen at the tissue level. Physiologically valid cellular potassium and sodium levels were seen, which demonstrates minimized redistribution artifact. Future tissue studies designed to correlate ion microscopic boron images to microscopic structure are feasible using cryogenic sample preparation and ion microscopy.
 ...
PMID:Subcellular localization of p-boronophenylalanine-delivered boron-10 in the rat 9L gliosarcoma: cryogenic preparation in vitro and in vivo. 793 57

The boron containing substances L- and D-carboranylalanine might be of interest for boron neutron capture therapy, BNCT. Cultured mouse melanoma B16 cells were analyzed regarding binding of these substances and some introductory studies on effects of thermal neutron irradiation were also carried out. Comparisons were made with two boron containing compounds, p-boronophenylalanine (BPA) and boronated thiouracil (BTU-1), previously proposed for BNCT of melanomas. The results showed that both L- and D-carboranylalanine bound well in the B16 cells whereas BTU-1 gave no, and BPA only a low, binding. Thus, both forms of carboranes bound better than the two previously proposed substances. The carboranes also bound rather well in two tested human melanoma cell lines, IGR1 and RPMI-7951. Both L- and D-carboranylalanine showed a certain binding to isolated melanin but were not incorporated during melanin synthesis. Cultured glioma cells, used for comparison, bound BPA and to some extent the carboranes. This indicates that the substances are not melanoma specific. The carboranes caused some acute detachment of monolayer growing cells but were not strongly toxic since they did not reduce the growth rate. The cells treated with L-carboranylalanine or BPA showed, after neutron irradiation, a clear decrease in survival compared to the controls whereas no or only small effects were seen for cells treated with D-carboranylalanine or BTU-1. These results were conflicting since BPA gave therapeutical effects although only small amounts were bound while D-carboranylalanine gave no significant therapeutical effect in spite of better binding. One explanation might be different intracellular localizations. This has to be studied in more detail.
 ...
PMID:Cellular binding of carboranylalanine and some effects of boron neutron capture. Analysis of cultured melanoma B16 cells. 794 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>