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PubMed2001

Tumor therapy with targeted atomic nanogenerators.

A single, high linear energy transfer alpha particle can kill a target cell. We have developed methods to target molecular-sized generators of alpha-emitting isotope cascades to the inside of cancer cells using actinium-225 coupled to internalizing monoclonal antibodies. In vitro, these constructs specifically killed leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate cancer cells at becquerel (picocurie) levels. Injection of single doses of the constructs at kilobecquerel (nanocurie) levels into mice bearing solid prostate carcinoma or disseminated human lymphoma induced tumor regression and prolonged survival, without toxicity, in a substantial fraction of animals. Nanogenerators targeting a wide variety of cancers may be possible.

Actinium↗

PubMed1977

Heavy particle therapy: pituitary tumors.

Therapy with 910 MeV alpha particles provides a treatment with no mortality and an extremely low morbidity and has been highly successful in the control of pituitary hormone hypersecretion and tumor growth. It is possible to deliver radiation doses to the pituitary gland that are sufficiently high to inhibit or destroy the tumor cells that cause abnormal secretory activity without damaging the surrounding structures. The data demonstrate the effectiveness of this form of treatment in acromegaly, non-functioning pituitary tumors, prolactin secreting adenomas, Cushing's disease and Nelson's syndrome.

Acromegaly↗

PubMed2006

High-energy resolution alpha spectrometry using cryogenic detectors.

Applications such as environment monitoring implying alpha emitters activity measurement associated with isotope identification, require high-energy resolution detectors. Conventional silicon detectors are inexpensive therefore widely used, although intrinsically limited in energy resolution. Thermal detection principle of cryogenic detectors introduces a breakthrough in alpha particle measurement. For the first time, spectra with 5.5 keV FWHM energy resolution have been obtained for several external alpha emitting sources using a copper-germanium bolometer specially developed for alpha spectrometry.

Alpha Particles↗

PubMed2002

Equations for modeling of grab samples of radon decay products.

A mathematical model of the process of collecting and analyzing a grab sample of radon decay products in air can be useful for a number ofpurposes. Among them is predicting the observed counts of alpha particles and/or beta particles (1) under various conditions of radon decay product equilibrium; (2) for various sampling, delay and counting times; and (3) for various counting efficiencies for the particles emitted by the collected decay products.

Air Pollutants, Radioactive↗

PubMed1975

Radiation effects on pig skin. Exposure to different densities of ionization.

The effects on pig skin from radiations producing different densities of ionization have been determined. For the qualities of radiation employed, erythema was produced at a dose range from 1,240 to 3,440 rads and ulceration at 1,250 to 5,000 rads. In no instance did a radiation-induced neoplasm develop. In determining dose response, two of the most important physical parameters, associated with time of appearance and extent of lesions, were found to be the size of the area irradiated and the density of ionization of the radiations used. These data, on normal tissue tolerance, should be a value in future programs initiated in experimental radiation therapy of both animal and human neoplasia utilizing protons, alpha particles, and carbon ions.

Alpha Particles↗

PubMed1991

Current status of bioassay procedures to detect and quantify previous exposures to radioactive materials. Bioassay Procedures Working Group.

This report was prepared by a working group established by the Oak Ridge Associated Universities (ORAU) for the purpose of assessing the current capabilities of bioassay methods that can be used to determine the occurrence and magnitude of a previous internal deposition of one or more radionuclides. The first five sections discuss general features of the use of in-vitro bioassay samples to achieve this purpose. The remainder of the report is focused on the possible use of urine bioassay procedures to detect and quantify internal depositions of radionuclides that may have occurred in United States occupation troops in Hiroshima or Nagasaki, Japan, prior to 1 July 1946, or to personnel who participated in atmospheric nuclear weapons tests conducted between 1945 and 1962. Theoretical calculations were made to estimate the quantities of various radionuclides produced in a 20-kiloton (kt) nuclear detonation that might still be present in measurable quantities in people today if they were exposed 25 to 40 y ago. Two radionuclides that emerged as good choices for this type of bioassay analysis were 90Sr, which emits beta particles, and 239,240Pu, which emits alpha particles. The current status and future prospects of chemical procedures for analyzing in-vitro urine bioassay samples for these two radionuclides were examined to determine the minimum amounts that could be detected with current methods and how much one might expect the sensitivity of detection to improve in the near future. Most routine 239,240Pu bioassay analyses involve detection by alpha spectrometry. The current minimum detectable amount (MDA) is about 0.74 mBq L-1 (20 fCi L-1), but this could be lowered to 74 muBq L-1 (2 fCi L-1). An MDA of 0.74 mBq L-1 (20 fCi L-1) is adequate for routine bioassay analyses but is too high to detect most uptakes of 239,240Pu that may have occurred 25 to 40 y ago. Methods under development that are or can be much more sensitive and have lower MDAs than alpha spectrometry for 239Pu are fission track analysis and mass spectrometry. Currently, the fission track analysis method has an MDA of about 19 muBq L-1), and this may eventually be lowered to 1.9 muBq L-1 (0.005 fCi L-1). The current MDA for 239Pu by mass spectrometry is about 7.4 mBq L-1 (200 fCi L-1), but the potential exists that it could be lowered to a value of about 0.37 muBq L-1 (0.01 fCi L-1).(ABSTRACT TRUNCATED AT 400 WORDS)

Feces↗

PubMed2003

Preliminary validation of computational procedures for a new atmospheric ionizing radiation (AIR) model.

A new computational procedure to determine particle fluxes in the Earth's atmosphere is presented. The primary cosmic ray spectrum has been modeled through an analysis of simultaneous proton and helium measurements made on high altitude balloon flights and spacecraft. An improved global fit to the data was achieved through applying a unique technique utilizing the Fokker-Plank equation with a non-linear rigidity-dependent diffusion coefficient. The propagation of primary particles through the Earth's atmosphere is calculated with a three-dimensional Monte Carlo transport program called FLUKA. Primary protons and helium nuclei (alphas) are generated within the rigidity range of 0.5 GV-20 TV uniform in cos2 theta. For a given location, primaries above the effective cutoff rigidity are transported through the atmosphere. Alpha particles are initially transported with a separate package called HEAVY to simulate fragmentation. This package interfaces with FLUKA to provide interaction starting points for each nucleon originating from a helium nucleus. Results from this calculation are presented and compared to measurements.

Alpha Particles↗

PubMed2001

Direct evidence for a bystander effect of ionizing radiation in primary human fibroblasts.

Bystander responses underlie some of the current efforts to develop gene therapy approaches for cancer treatment. Similarly, they may have a role in strategies to treat tumours with targeted radioisotopes. In this study we show direct evidence for the production of a radiation-induced bystander response in primary human fibroblasts. We utilize a novel approach of using a charged-particle microbeam, which allows individual cells within a population to be selected and targeted with counted charged particles. Individual primary human fibroblasts within a population of 600-800 cells were targeted with between 1 and 15 helium ions (effectively, alpha-particles). The charged particles were delivered through the centre of the nucleus with an accuracy of +/- 2 micrometer and a detection and counting efficiency of greater than 99%. When scored 3 days later, even though only a single cell had been targeted, typically an additional 80-100 damaged cells were observed in the surviving population of about 5000 cells. The yield of damaged cells was independent of the number of charged particles delivered to the targeted cell. Similar results of a 2-3-fold increase in the background level of damage present in the population were observed whether 1 or 4 cells were targeted within the dish. Also, when 200 cells within one quadrant of the dish were exposed to radiation, there was a 2-3-fold increase in the damage level in an unexposed quadrant of the dish. This effect was independent of the presence of serum in the culture medium and was only observed when a cell was targeted, but not when only the medium was exposed, confirming that a cell-mediated response is involved.

Alpha Particles↗

PubMed1984

Determination of absorbed dose to blood, kidneys, testes and thyroid in mice injected with 211At and comparison of testes mass and sperm number in x-irradiated and 211At treated mice.

Male mice were injected with 211At and the total absorbed dose to the whole blood, kidneys, testes and thyroid was determined. Extrapolation to man shows a close agreement with the predictions of the International Commission on Radiological Protection (ICRP) for the absorbed dose to human blood, kidneys and testes, but the absorbed dose to the thyroid is about 200 times greater than the ICRP prediction. Comparison of the reduction in testes mass and in sperm numbers 28 days after mice were injected with 211At, or exposed to x rays, indicates a factor of about four for the greater effectiveness of 211At alpha particles over 250 kVcp x rays for the induction of effects.

Alpha Particles↗

PubMed1997

Can occult metastases be treated by radioimmunotherapy?

BACKGROUND: Tumor lesions in the millimeter (mm) range may escape detection with nuclear medicine imaging methods (including single photon emission computed tomography [SPECT]) using radiolabeled monoclonal antibodies (MoAbs). We hypothesized that these lesions still could receive a potentially therapeutic radiation absorbed dose, and therefore should be treated, despite the lack of detection. METHODS: To simulate this situation, 2-mm beads (0.004 mL) containing approximately 1.15 microCi of iodine-131 (131I) were used. The beads were placed centrally in a 1200-mL liver phantom containing approximately 3 mCi of 131I. The resultant activity concentration on the beads was approximately 288 microCi/mL compared with approximately 2.5 microCi/mL in the phantom, corresponding to a maximum tumor uptake of approximately 0.3% injected dose per gram (%ID/g) if 100 mCi of 131I-labeled immunoglobulin G were administered. The phantom, containing the beads, was imaged by both planar and SPECT techniques at hypothetical Day 1 (time of maximum tumor uptake) and at hypothetical Day 7 to examine the improved target-to-nontarget ratio over time. In addition to imaging the beads, the radiation absorbed dose to the simulated lesions from the beta component emissions of 131I was calculated using absorbed fractions based on Berger's point kernels. RESULTS: Regardless of the conditions used, the beads could not be observed by either planar or SPECT imaging. However, the radiation-absorbed dose to the simulated lesion was calculated to be as high as approximately 6200 centigray (cGy), with an average dose rate of approximately 89.5 cGy/hour. CONCLUSIONS: This simulation demonstrates that a relatively high absorbed dose and dose rate can be delivered to mm-sized lesions not observed by conventional nuclear imaging methods, and that these lesions should be considered for radioimmunotherapy with 1311 MoAbs. However, for micrometastases of <1 mm, other radionuclides with shorter path length beta particles than 131I, Auger electrons, or alpha particles should be considered.

Humans↗

PubMed1999

Postoperative treatment of glioblastoma with BNCT at the petten irradiation facility (EORTC protocol 11,961).

The boron neutron capture therapy is based on the reaction occurring between the isotope 10B and thermal neutrons. A low energy neutron is captured by the nucleus and it disintegrates into two densely ionising particles, Li nucleus and He nucleus (alpha particle), with high biological effectiveness. On the basis of comprehensive preclinical investigations in the frame of the European Collaboration with Na2B12H11SH (BSH), as boron delivery agent, the first European phase I, clinical trial was designed at the only available epithermal beam in Europe, at the High Flux Reactor, Petten, in the Netherlands. The goal of this study is to establish the safe BNCT dose for cranial tumors under defined conditions. BNCT is applied as postoperative radiotherapy in 4 fractions, after removal of the tumor for a group of patients suffering from glioblastoma, who would have no benefit from conventional treatment, but have sufficient life expectancy to detect late radiation morbidity due to BNCT. The starting dose is set at 80% of the dose where neurological effects occurred in preclinical large animal experiments following a single fraction. The radiation dose will be escalated, by constant boron concentration in blood, in 4 steps for cohorts of ten patients, after an observation period of at least 6 months after the end of BNCT of the last patient of a cohort. The adverse events on healthy tissues due to BSH and due to the radiotherapy will be analysed in order to establish the maximal tolerated dose and dose limiting toxicity. Besides of the primary aim of this study the survival will be recorded. The first patient was treated in October 1997, and further four patients have been irradiated to-date. The protocol design proved to be well applicable, establishing the basis for scientific evaluation, for performance of safe patient treatment in a very complex situation and for opening the possibility to perform further clinical research work on BNCT.

Brain Neoplasms↗

PubMed1993

The distribution of 210Po in human bone.

Recent measurements of natural radioactivity in human bone using alpha particle autoradiography have indicated that the alpha activity concentration in the bone marrow is similar to that found in the calcified bone. This paper describes radiochemical measurements made on the calcified bone and the associated bone marrow from three human femurs. A technique was developed to separate and analyse these tissues for the principal naturally-occurring alpha emitter, 210Po. In all cases the activity concentration of the calcified bone was greater than that of the associated bone marrow. As predicted by the metabolic models used by International Commission on Radiological Protection, the majority of the 210Po in whole bone was found to be in the calcified region.

Aged↗

PubMed1990

Differential neutron energy spectra measured on spacecraft in low Earth orbit.

Two methods for measuring neutrons in the range from thermal energies to dozens of MeV were used. In the first method, alpha-particles emitted from the 6Li(n,alpha)T reaction are detected with the help of plastic nuclear track detectors, yielding results on thermal and resonance neutrons. Also, fission foils are used to detect fast neutrons. In the second method, fast neutrons are recorded by nuclear photographic emulsions (NPE). The results of measurements on board various satellites are presented. The neutron flux density does not appear to correlate clearly with orbital parameters. Up to 50% of neutrons are due to albedo neutrons from the atmosphere while the fluxes inside the satellites are 15-20% higher than those on the outside. Estimates show that the neutron contribution to the total equivalent radiation dose reaches 20-30%.

Cosmic Radiation↗

PubMed2000

Experimental kerma coefficients of biologically important materials at neutron energies below 75 MeV.

The present work summarizes our results already published on cross sections and partial kerma coefficients for hydrogen, carbon, and oxygen and then applies them for determining experimental partial and total kerma coefficients of composite biologically important materials. Double-differential cross sections for light-charged particle production (proton, deuteron, triton, and alpha particle) induced by fast neutrons on hydrogen, carbon, and oxygen have been experimentally measured at several incident energies from 25 to 75 MeV. The measurements covered the laboratory angular range 20 degrees to 160 degrees and were extended to very forward and very backward angles by using a reliable extrapolation procedure. Energy-differential, angle-differential, and total production cross sections were derived from the measured data. The experimental methods and data reduction procedures are briefly presented here. The experimental cross sections were compared to existing data in the literature for nucleon-induced reactions and against prediction of nuclear models. Partial and total elemental kerma coefficients were deduced on the basis of the measured cross sections. Procedures for extrapolating the partial kerma coefficients down to the reaction threshold energies for each of the measured ejectile species have been applied to carbon and oxygen. A simple-to-use analytical formula to describe the experimental hydrogen kerma coefficients was proposed which provides the recoil kerma coefficients in the incident neutron energy range 0.3 to 100 MeV. The present article reports for the first time experimental partial kerma coefficients for composite materials of biological interest. Resulting total kerma coefficients are compared to theoretical predictions and to other experimental data.

Algorithms↗

PubMed2005

Combination of boron and gadolinium compounds for neutron capture therapy. An in vitro study.

In neutron capture therapy, the therapeutic effect of the boron compound is based on alpha particles produced by the B(n, alpha) reaction while with the gadolinium compound the main radiation effect is from gamma rays derived from the Gd(n, gamma) reaction. The uptake and distribution within the tumor may be different among these compounds. Thus, the combination of the boron and gadolinium compounds may be beneficial for enhancing the radiation dose to the tumor. Chinese hamster fibroblast V79 cells were used. For the neutron targeting compounds, 10B (BSH) at 0, 5, 10, and 15 ppm, and 157Gd (Gd-BOPTA) at 0, 800, 1600, 2400, 3200, and 4800 ppm, were combined. The neutron irradiation was performed with thermal neutrons for 30 min. (neutron flux: 0.84 x 10(8) n/cm2/s in free air). The combination of the boron and gadolinium compounds showed an additive effect when the gadolinium concentration was lower than 1600 ppm. This additive effect decreased as a function of gadolinium concentration at 2400 ppm and resulted in no additive effect at more than 3200 ppm of gadolinium. In conclusion, the combination of the boron and gadolinium compounds can enhance the therapeutic effect with an optimum concentration ratio. When the gadolinium concentration is too high, it may weaken the boron neutron capture reaction due to the high cross-section of gadolinium compound against neutrons.

Animals↗

PubMed1981

Mitochondrial anomalies in renal oncocytes induced in rat by N-nitrosomorpholine.

Renal oncocytes were induced in male Sprague-Dawley rats by oral application of N-nitrosomorpholine (NNM) in a concentration of 12 or 50 mg per 100 ml drinking water and analysed by transmission electron microscopy. The oncocytes exhibited mitochondrial anomalies which were very similar to those of human oncocytoma oncocytes. The most striking mitochondrial changes were an unusually large number of the organelles and an excess of the cristae mitochondriales. The shape of the mitochondria varied from round and oval to extremely elongated slender or cup-shaped organelles often piled up to form complex bodies. Rarely large ramifying mitochondria were found. In addition to transversely orientated cristae or tubules the inner mitochondrial membranes frequently formed dense stacks of unusually long cristae often arranged longitudinally. In some mitochondria straight and strictly parallelly arranged neighbouring cristae were found to be connected by a paracrystalline array of pillars bridging the mitochondrial matrix. In the majority of oncocytes the mitochondrial matrix contained prominent dense granules (diameter 30-50 nm), but sometimes these were rare or absent. Individual mitochondria of many oncocytes showed membrane-bound deposits of glycogen particles which usually formed rosettes (alpha-particles) with a diameter of about 80 nm. Partitioned mitochondria were not seen. Often autophagic vacuoles containing portions of degraded mitochondria and dense bodies, probably autophagosomes, were observed. The nature and significance of the oncocytes remains unclear, but we suggest from these and earlier experimental results that oncocytes represent a special type of a neoplastically transformed cell which usually has only a low potential for "autonomous" growth. Renal oncocytes induced in rats by chemical carcinogens appear to be an excellent experimental model for the further investigation of this cell type.

Animals↗

PubMed1983

Effect of HZE particles and space hadrons on bacteriophages.

The effect of high energy (HZE) particles and high energy hadrons on T4Br+ bacteriophage was analyzed. The experiments were done in orbital flight, on high mountains, on an accelerator, and with an alpha particle source. We studied the survival rate of the bacteriophage, the mutation frequency, the mutation spectrum and the revertability under the action of chemical mutagens with a known mechanism of action on DNA. It was found that the biological efficiency of HZE particles and high energy hadrons is greater than that of gamma radiation. The spectra of mutations produced by these mutations and the mechanisms of their action are also different. These effects were local, because of the mode of interaction of the radiant energy with biological objects, and depended on the linear energy transfer (LET). The modes have now been experimentally defined.

Alpha Particles↗

PubMed2000

Radiation effects in spheroids of cells exposed to alpha emitters.

PURPOSE: To simulate spheroids of cells and use the spheroid models to establish methods of calculating cell survival following exposure to alpha irradiation from decays of 211At and 213Bi. METHODS: Using a Monte Carlo technique, two models of spheroids of cells were generated in which cells either did not or were allowed to overlap. At 40% packing of the volume it is shown that the two models are equivalent for longer-ranged alpha particles. The overlapping model was used to examine the effects of spheroid size and cell packing on cell survival. Cell survival was also calculated for different distributions of alpha decays such as uniform distribution within the spheroid, external to the spheroid and as a shell on the periphery of the spheroid. RESULTS: Three examples of the cell structure of the spheroids are shown. Detailed calculations show that cell survival decreases from 57% to 37% as the spheroid diameter increases from 75 microm to 225 microm for an average of one 211At decay per cell and 50% packing. Increasing the packing of the cells in the spheroid from 40% to 70% reduces survival from 46% to 26% for 200 microm diameter spheroids for one 211At or 213Bi decay per cell. The presence of small regions of unlabelled cells within the spheroids does not significantly change cell survival. CONCLUSIONS: Monte Carlo programmes generating spheroids of cells and their subsequent use to score cell survival for alpha irradiation should be useful in the design and interpretation of work on spheroids of cells in vitro and the application of such modelling to the study of very small tumours in vivo. Copies of the programmes are available from the author on request.

Alpha Particles↗