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PubMed1996

Boron neutron capture therapy of brain tumors: past history, current status, and future potential.

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.

Boron Compounds↗
PubMed1987

Determination of 18O by prompt nuclear reaction analysis: application for measurement of microsamples.

A method is described for the routine determination of 18O concentrations in microsamples of biological fluids. The method utilizes the prompt nuclear reaction 18O(p, alpha o)15N, and 846-keV protons from a 3-MeV Van de Graaff Accelerator are focused on approximately 2,000-A-thick Ta2O5 targets prepared by anodic oxidation from 50-microliter samples of water distilled from blood or other biological fluids. The broad cross section of the resonance peak for this nuclear reaction (47 keV) ensures high yields, especially at small reaction angles, and the high-energy alpha particles produced by the reaction (4 MeV) are readily separated from scattered protons by the use of an aluminized Mylar foil of suitable thickness. Background levels of 18O (0.204 atom%) can be detected with run times of approximately 5-8 min, and the sensitivity of the method is of the order of 0.05 atom %. Experimental error due to sample preparation was found to be 1.7%, and counting errors were close to theoretical limits so that total error was of the order of 2.5%. Duplicate samples were analyzed by use of the 18O(p, alpha o)15N reaction at Lucas Heights, Australia, and the 18O(p,n)18F reaction by the method of Wood et al. (Anal. Chem. 47: 646-650, 1975) at the University of California, Los Angeles, and the agreement was excellent (y = 1.0123x - 0.0123, r = 0.991, P less than 0.001). The theoretical limitations and the general applicability of the method in biological studies designed to estimate the rate of metabolism of free-ranging animals are discussed.

Animals↗
PubMed2002

Feasibility of a neutron detector-dosemeter based on single-event upsets in dynamic random-access memories.

The feasibility was investigated of a solid-state neutron detector/dosemeter based on single-event upset (SEU) effects in dynamic random-access memories (DRAMs), commonly used in computer memories. Such a device, which uses a neutron converter material to produce a charged particle capable of causing an upset, would be light-weight, low-power, and could be read simply by polling the memory for bit flips. It would have significant advantages over standard solid-state neutron dosemeters which require off-line processing for track etching and analysis. Previous efforts at developing an SEU neutron detector/dosemeter have suffered from poor response, which can be greatly enhanced by selecting a modern high-density DRAM chip for SEU sensitivity and by using a thin 10B film as a converter. Past attempts to use 10B were not successful because the average alpha particle energy was insufficient to penetrate to the sensitive region of the memory. This can be overcome by removing the surface passivation layer before depositing the 10B film or by implanting 10B directly into the chip. Previous experimental data show a 10(3) increase in neutron sensitivity by chips containing borosilicate glass, which could be used in an SEU detector. The results are presented of simulations showing that the absolute efficiency of an SEU neutron dosemeter can be increased by at least a factor of 1000 over earlier designs.

Computer Storage Devices↗
PubMedDate not supplied

Factors affecting use of CR-39 surface monitor technology to estimate past exposure to indoor radon.

In an epidemiologic study investigating influences of life-style and environment on lung cancer risk, CR-39 alpha-particle detectors, identified here as surface monitors, were affixed to subjects' selected household glass, ceramic, or enameled objects to measure residual radioactivity form embedded radon (Rn) decay products. The purpose was to estimate past cumulative indoor Rn concentrations to which the object was exposed to infer past exposures of the subjects. This approach was used to supplement exposure information obtained by methods traditionally used in Rn epidemiologic studies. In addition, surface monitors were affixed to objects of selected study subjects with complete exposure information to evaluate whether surface monitors provided estimates of cumulative past residual Rn exposure comparable to estimates obtained from year-long, ambient alpha track-etch measurements in each present and previous residence. These ambient measurements were time-weighted to estimate integrated exposure of objects and were adjusted for decay and ingrowth so as to be comparable to surface monitor measurements. A regression relationship was estimated between the two estimates of cumulative RN exposure. Surface monitor measurements had a satisfactory correlation (0.63) with adjusted ambient Rn measurements for new, nonceramic objects. Although not included in the study design, factors that might affect use of the technology were also investigated. Regression relationships were compared in graduated smoking environment (as judged by the subjects) to investigate possible differential plate out of radon progeny. In addition, regression relationships for windows were compared with those for other objects to investigate whether there was a significant difference between windows and other objects. It has been suggested that windows may have a higher plate out rate because of locally increased air flow. Results suggested that surface monitor information was useful to fill time gaps in estimates of historical radon exposure data obtained by ambient measurements. Glass samples provided the best correlation. Ceramic materials sometimes provided excessively high radon estimates, probably due to glazes that contained significant uranium or thorium. Due to small sample sizes, investigations of other factors were inconclusive.

Air Pollutants, Radioactive↗
PubMed1988

In vitro induction of chromosomal aberrations in human lymphocytes, with and without boron 10, by radiations concerned in boron neutron capture therapy.

A beam consisting of mainly 24 keV neutrons has been constructed for radiobiological studies to evaluate the potential of these particles for treating deep tumours by the boron capture reaction. The induction of chromosomal aberrations in human lymphocytes in vitro was examined and a linear dose effect with a relative biological effectiveness similar to fission neutrons was obtained. For samples placed at depths in a plastic phantom the aberration yields declined with depth at a rate matching the fall in the sum of dose due to proton recoils and neutron capture in nitrogen 14. The presence of boron 10 at 30 micrograms ml-1 did not affect the aberration yield. By using the mixed sample method, the probability of interphase death or mitotic delay in cells crossed by an alpha particle or lithium-7 ion produced in the boron capture reaction was shown to be close to 1.0. Thus these cells are prevented from coming to mitosis in culture. The implications for boron capture therapy are that this filtered beam has a "high LET" effect which could lead to poor normal tissue sparing. However there may be a significant therapeutic advantage due to a high probability of killing tumour cells that have incorporated boron 10.

Boron↗
PubMed2006

Confocal fluorescent imaging of tracks from heavy charged particles utilising new Al2O3:C,Mg crystals.

A completely optical, non-destructive imaging of tracks in a fluorescent crystal provides a new way to detect and to assess doses from heavy charged particles and neutrons. The technique combines confocal fluorescent microscopy with a new radiation-sensitive, luminescent material based on aluminium oxide single crystals doped with carbon, magnesium and having aggregate oxygen vacancy defects (Al2O3:C,Mg). Radiation-induced colour centres in the new material have an absorption band at 620 nm and produce fluorescence at 750 nm with a high quantum yield and a short, 75 +/- 5 ns, fluorescence lifetime. Three-dimensional spatial distribution of fluorescent intensity allows one to obtain depth-dose distributions and to discriminate between high- and low-linear energy transfer radiations. Images of single tracks produced by different types of radiation have been obtained. Irradiations with a calibrated 241Am alpha source showed high efficiency for track detection. Thermal neutrons were detected using a nuclear reaction with a 6LiF radiator and production of alpha particles and tritium ions. Fast neutrons were detected using recoil protons produced in a polyethylene radiator installed in front of the crystalline detector. Three-dimensional reconstruction of a recoil proton propagating through the crystal was demonstrated.

Aluminum Oxide↗
PubMed2004

Morphological features of the microdistribution of naturally occurring 10Pb/2l0Po and 226Ra in the teeth of children and juveniles.

PURPOSE: To examine the microdistribution of natural alpha-radioactivity in deciduous teeth of children and the permanent teeth of juveniles extracted for orthodontic purpose from across the UK. MATERIALS AND METHODS: The microdistribution of 210Pb-supported 210Po and 226Ra in 708 deciduous and permanent teeth and 32 foetal teeth was measured on 1442 TASTRAK alpha-particle track detectors. RESULTS: Of the various findings, a number are of special interest. Around half of the 210Pb activity in the outer enamel of deciduous teeth appears to have been acquired in utero as a result of transplacental transfer. In deciduous and permanent teeth, 226Ra is concentrated mainly in the circumpulpal region, while the highest levels of 210Po are on the highly calcified outer enamel surface. Furthermore, activity concentrations recorded on this surface were In-normally distributed. CONCLUSIONS: 210Pb-supported 210Po activity on the outer enamel surface of permanent teeth constitutes an assay of cumulative environmental exposure with which to assess exposure in bone, both in utero and in childhood. Such assessment can be used to study geographical variations in the alpha-activity in teeth. More work is also required to determine the concentrations of both 210Po and 210Pb in the foetal skeleton.

Adolescent↗
PubMed1981

[Histological, electron microscopic and biochemical study of the rat liver in experimental cardiomyopathy].

Morphological, electron microscopic, and biochemical studies of the livers of rats with experimental autoimmune cardiomyopathy were carried out. Morphological alterations of the liver included changes in hepatocytes, significant deposition of glycogen in liver cells, fatty dystrophy, signs of necrobiosis and necrosis in some parts of the liver. Electron microscopic studies of intracellular localization of glycogen revealed its accumulation in the cytoplasm, glycogen granules being represented mostly by alpha-particles. Lysosomes filled with glycogen were also demonstrated. These data are in good accord with the results of biochemical studies. The experimental results suggest possible causes of increased content of glycogen in the cytoplasm and lysosomes of liver cells in animals with experimental autoimmune cardiomyopathy, as compared with normal animals. The relationship between disorders in glycogen and lipid metabolism in this disease is discussed.

Animals↗
PubMed1992

Dosimetric implications of pulmonary macrophage clusters observed within lungs of rats that have inhaled enriched UO2 particles.

Twenty-four Fischer 344 rats were exposed to enriched uranium dioxide (UO2) aerosols to give a mean initial lung burden of 291 +/- 89 (SD) micrograms. Groups of rats were killed at 1, 7, 180, 360, 540, and 720 days post-inhalation (PI). Their lungs were fixed and inflated. Sections cut from all five lung lobes were used to prepare CR-39 neutron-induced 235U fission fragment autoradiographs. A single traverse across a CR-39 autoradiograph of a tissue section, from the left lung of all the rats, was made using a motorized microscopic stage. The traverse was divided into 10 fields. The track counts per field were used to test for homogeneity of track distribution and to assess if there was any tendency for tracks to be related to the peripheral region of the lung. Full raster scans across the entire tissue image were made on left lung autoradiographs from two animals killed at each time point to assess the homogeneity of fission fragment track distribution throughout the entire section. There was no evidence of any temporal change in the proportion of tracks associated with the lung periphery. At all time points PI, the track distribution was significantly nonhomogeneous, suggesting a nonuniform pattern of tissue irradiation from the 234U alpha particles. At time points from 180 to 720 days PI, large clusters of macrophages were observed in some of the sections taken from all five lung lobes. The total number of macrophage clusters increased with time PI. These macrophage clusters produced many 235U fission fragment tracks within the CR-39 autoradiographs.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed2001

Correlated hit probability and cell transformation in an effect-specific track length model applied to in vitro alpha irradiation.

In estimating the risk from low doses of alpha particles such as those emitted by radon progeny, it is important to consider the correlation between cellular inactivation and transformation that can exist at the cellular level. A phenomenological model of radiation-induced cellular inactivation and transformation at this level is presented here which incorporates aspects of a state vector model of radiation carcinogenesis and of correlated hit probabilities for inactivation and transformation. The general form of the model assumes that both inactivation and initial initiation damage are produced through the interaction of sublesions induced by radiation passing through cell nuclei, with the production of sublesions governed by hit probabilities and a characteristic probability-per-unit track length. The inactivation and initiation events are partially correlated through the use of hit probabilities. In addition, promotional events are incorporated for the case of cellular transformation based on a previously published state vector model. The model provides good fits to available data on the relationship between inactivation, transformation and LET for doses of alpha above 0.1 Gy in the range of LETs commonly produced by radon and progeny; by "good fits" we mean here the ability to yield the correct shapes of dose-response data using parameter values that vary smoothly with LET and using inactivation parameters that are applied consistently between inactivation and transformation assays. The resulting model correctly predicts recent findings indicating an increased transformation frequency per surviving cell when a population receives a distribution of hits compared to irradiation where all cells receive the same number of hits.

Animals↗
PubMed2004

Cytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate.

HER-2 has been implicated in the oncogenesis of human prostate cancer (CaP) and is the target of a new treatment for metastatic breast cancer using the humanised monoclonal antibody (MAb) trastuzumab (Herceptin). In this study, a novel alpha-particle emitting [213Bi]Herceptin construct, which targets the HER-2 extracellular domain on CaP cells, was prepared and evaluated in vitro. We used immunocytochemistry, flow cytometry and Western blot analysis to examine the expression of HER-2 in a panel of established human CaP cell lines, used the MTS assay to evaluate the cytotoxicity of 213Bi-Herceptin on these cell lines and the TUNEL assay to document apoptosis. The results indicate that LNCaP-LN3 cells express high levels of HER-2 protein, in contrast, DU 145 cells express low to medium levels, and PC-3 cells express an undetectable level of HER-2 protein. 213Bi-Herceptin was specifically cytotoxic to LNCaP-LN3 cells in a concentration-dependent fashion, cause the cells to undergo apoptosis, whereas DU 145 showed an HER-2 level-dependent response to 213Bi-Herceptin cytotoxicity. In contrast, PC-3 cells were resistant to 213Bi-Herceptin-induced cytotoxicity. The 213Bi-Herceptin induced apoptosis in LNCaP-LN3 cells could be inhibited by incubation with unlabeled Herceptin. Our results suggest that 213Bi-Herceptin alpha-conjugate might be a promising new agent for the treatment of preangiogenic cancer cell clusters or micro-metastases with high levels of HER-2 expression.

Antibodies, Monoclonal↗
PubMed1978

[Production of 67Ga, 68Ga by bombardment of natural zinc target with alpha and 3He particles (author's transl)].

In order to determine the optimum irradiation condition for the production of 67Ga and 68Ga, used in nuclear medicine, excitation function and thick-target yield curves were obtained for alpha and helium-3 reactions of natural zinc. With the initial alpha energy of 25 MeV, the thick-target yield of 67Ga was found to be 165 muCi/muA.hr at the end of bombardment and the 66Ga contamination could be reduced to less than 1% after about 3 days of cooling. 68Ga could be obtained by milking from 68Ge. With the alpha energy range of 17-40 MeV, the thick-target yield of 68Ga was 1.2 muCi/muA.hr at the end of bombardment.

Alpha Particles↗
PubMed1988

Ultrastructural study of the alveolar-capillary membrane and the tubular endoplasmic reticulum in alveolar type I cells of the caprine lung.

The ultrastructural features of alveolar type I cells of the goat lung were studied by using vascular perfusion and direct airway instillation of fixatives. The morphological features of smooth endoplasmic reticulum (SER) were characterized by measuring the diameter of individual SER tubules which conformed in size and appearance to the tubular endoplasmic reticulum (TER) already described in various types of epithelium. The TER appeared as large tubular aggregates in a palisade arrangement; these aggregates ramified into various areas of the extended cytoplasm of alveolar type I cells. The TER also existed as a mixture of short cisternae and vesicles, and glycogen alpha particles were present in the non-perikaryonic portion of the cell. The different forms of TER had varying relationships to the plasmalemma. The interchangable configurations seen in the structure of TER indicated the functional modalities of the cells and were comparable to similar structural modifications in electrolyte-secreting cells. The role of TER, microtubules, and large populations of endocytic vesicles in the alveolar type I cells in the goat lung is examined in the context of physiological eructation of rumenal gases and the absorption of electrolyte-rich fluids which escape into the lung at each eructation in ruminants.

Animals↗
PubMed1994

Lung cancer mortality and airways obstruction among metal miners exposed to silica and low levels of radon daughters.

Starting from a cross-sectional survey in 1973, the mortality of two cohorts of Sardinian metal miners was followed through December 31, 1988. In mine A, the quartz concentration in respirable dust ranged between 0.2% and 2.0% and the exposure to radon daughters averaged 0.13 working level (WL), with the highest estimated cumulative exposure around 80-120 WLM. In mine B, the silica content was much higher (6.5-29%), but exposure to radon daughters was significantly lower than in mine A. More than 98% of the overall work force in 1973 (1,741 miners) entered the cohort, providing 25,842.5 person-years. Smoking, occupational history, chest radiographs, and lung function tests were available for the cohort members at admission. Mortality for all causes was slightly lower than expected. A significant excess for nonmalignant chronic respiratory diseases was noticed in both mines. Twenty-four subjects died of lung cancer, 17 from mine A (SMR: 128; 95% confidence interval [CI]: 75-205) and 7 from mine B (SMR: 85; 95% CI: 34-175). The SMR for lung cancer was highest among the underground workers from mine A (SMR: 148; 95% CI: 74-265), with a significant upward trend by duration of employment in underground jobs. Mine B underground miners showed lung cancer SMRs close to 100 without a significant trend by duration of employment. Among underground miners with spirometric airways obstruction in 1973, those from mine A showed the highest risk (SMR: 316; 95% CI: 116-687). The relationship did not change after adjusting for age and smoking. Based on the present findings, crystalline silica per se does not appear to affect lung cancer mortality. A slight association between lung cancer mortality and exposure to radon daughters, though within relatively low levels, may be considered for underground miners from mine A. Impaired pulmonary function may be an independent predictor of lung cancer and an important risk factor enhancing the residence time of inhaled carcinogens, i.e., alpha particles or PAHs, by impairing their bronchial and alveolar clearance.

Adolescent↗
PubMed1980

Osteometry and autoradiography of the long bones of skeletons of women exposed to internal radiation at 13--19 years of age.

Lengths of long bones of skeletons were examined in 25 women first exposed to large skeletal doses of radiation (alpha particles from radium) at the age of 13--19 years. Mean lengths did not differ significantly between two subgroups based on age at first exposure to radiation (i.e., 13--16 vs. 17--19 years). Autoradiographs of femora of some women who ingested radium at 13-15 years of age showed evidence for bone growth when blood levels of radium were low (i.e., after ingestion of radium). These findings indicate no detectable effect of large skeletal doses of radiation on growth in adolescent and post-adolescent periods.

Adolescent↗
PubMed2005

Complex chromosome aberrations persist in individuals many years after occupational exposure to densely ionizing radiation: an mFISH study.

Long-lived, sensitive, and specific biomarkers of particular mutagenic agents are much sought after and potentially have broad applications in the fields of cancer biology, epidemiology, and prevention. Many clastogens induce a spectrum of chromosome aberrations, and some of them can be exploited as biomarkers of exposure. Densely ionizing radiation, for example, alpha particle radiation (from radon or plutonium) and neutron radiation, preferentially induces complex chromosome aberrations, which can be detected by the 24-color multifluor fluorescence in situ hybridization (mFISH) technique. We report the detection and quantification of stable complex chromosome aberrations in lymphocytes of healthy former nuclear-weapons workers, who were exposed many years ago to plutonium, gamma rays, or both, at the Mayak weapons complex in Russia. We analyzed peripheral-blood lymphocytes from these individuals for the presence of persistent complex chromosome aberrations. A significantly elevated frequency of complex chromosome translocations was detected in the highly exposed plutonium workers but not in the group exposed only to high doses of gamma radiation. No such differences were found for simple chromosomal aberrations. The results suggest that stable complex chromosomal translocations represent a long-lived, quantitative, low-background biomarker of densely ionizing radiation for human populations exposed many years ago.

Chromosome Aberrations↗
PubMed2002

Microsatellite instability in thorotrast-induced human intrahepatic cholangiocarcinoma.

Thorotrast, a colloidal suspension of radioactive (232)ThO(2) that emits alpha particles, was used as a radiographic contrast during World War II. It is known to induce liver cancers, most frequently ICC, decades after injection. Since radiation induces genomic instability, we analyzed MSI in Thorotrast-induced ICC. The frequency of MSI(+) cases was 62.5% in Thorotrast ICC, whereas it was 22.7% in non-Thorotrast ICC. However, frameshift mutations of mononucleotide repeats were not observed in Thorotrast ICC. In addition, the MSI(+) phenotype was not associated with the quantity of Thorotrast deposited or the latency period of ICC induction. Promoter regions of both the hMLH1 and the hMSH2 MMR genes tended to be hypermethylated in the tumor part compared to the adjacent nontumor part in Thorotrast ICC. Methylation of the hMLH1 promoter was associated with the MSI(+) phenotype in Thorotrast ICC. In contrast, methylation status of these promoter regions was not related to MSI in non-Thorotrast ICC cases. These findings suggest that MSI induced by exposure to Thorotrast mainly reflects clonal expansion of cancer cells and is partly due to inactivation of hMLH1 by hypermethylation.

Adaptor Proteins, Signal Transducing↗