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PubMed1996

Influence of cell position relative to planar alpha-particle sources on survival and preneoplastic transformation of primary rat tracheal epithelial cells.

Rat tracheal epithelial cells exposed directly on planar 210Po sources exhibited exponential cell killing; however, no significant increase in induction of preneoplastic transformation was observed over a range of alpha-particle fluences (0.017-0.050 micron-2). In contrast, up to 10-fold increases in frequencies of preneoplastic transformants, above control levels, were observed after exposure of rat tracheal epithelial cells to similar alpha-particle fluences on 238Pu and 241Am sources. Two alternative hypotheses are evaluated as an explanation for this apparent difference in the biological effect of alpha particles emitted from different sources: (a) possible interactions between effects produced by alpha particles and by low-energy photons, which occur with 238Pu and 241Am but not with 210Po; and (b) the influence of spatial relationships between exposed cells and the surface of the planar source. The data suggest that cell-to-source spatial relationships affect both survival and transformation markedly.

Alpha Particles↗

PubMed1999

[Identification of cDNA fragments related to alpha particles radiation induced neoplastic transformation of rat tracheal epithelial cells].

OBJECTIVE: To isolate genes involved in neoplastic transformation induced by alpha-particles. METHODS: The differential display technique was used to identify differentially expressed mRNA species between primary and neoplastic transformed rat tracheal epithelial (RTE) cells induced by alpha particles. RESULTS: 15 differentially displayed gene fragments were cloned and sequenced. Seven novel ESTs were submitted to GenBank. Homology searching revealed that clone ZG35 was highly homologous to rat Annexin I gene which was thought to be involved in mitogenic signal transduction as a substrate of epidermal growth factor receptor/kinase. Clone ZC52 was nearly identical to a novel rattus norvegicus gene for carboxylesterase precursor, clone ZG52 was 3' similar to human SRPK2 gene suggesting it may be a novel SRPK2 related gene involved in pre-mRNA splicing. Clone ZA73 was a novel gene fragments, and clone ZC66 was highly homologous to rat nucleoside diphosphate kinase gene or metastasis suppressor gene nm23, sequence analysis suggested that nm23 might be mutated in the transformed RTE cells. Northern hybridization confirmed the above gene or gene fragments to be up-regulated in the transformed RTE cells. CONCLUSION: These results provide clues to elucidate the mechanisms of radiation oncogenesis and suggest that Annexin I, carboxylesterase precursor gene, ZG52 and nm23 may be involved in the neoplastic transformation induced by alpha-particles radiation.

Alpha Particles↗

PubMed1989

[Estimation of the energy fraction emitted by alpha particles in the mineralized part of trabecular bone which is absorbed in the bone marrow].

The cells at particular carcinogenic risk in the skeleton are haematopoietic stem cells of the marrow, which are predominantly distributed throughout the haematopoietic marrow within the trabecular bone. The Monte Carlo method for estimating the fraction of the energy of alpha particles emitted in a volume of the mineral part of the bone which is deposited in the marrow is described. The relationship between the absorbed fraction (AF) of the alpha particles and their energy was found to be linear. AF (Red Marrow----Trabecular Bone) is calculated to be 0.016 for the radionuclides emitting 3 MeV alpha particles and 0.080 for those emitting 8 MeV alpha particles. As radionuclides are for purposes of bone dosimetry dichotomously classified as surface and volume seekers, the estimation of energy deposition in the skeletal target organs can be highly dependent on this classification because of complicated geometric relationships between the source and target regions.

Alpha Particles↗

PubMed1999

Values of "S," , and <(z1)2> for dosimetry using alpha-particle emitters.

In a recent paper [J. Nucl. Med. 38, 1923-1929 (1997)], the authors presented a dosimetry system which combines the computational ease of the MIRD schema with additional information provided by microdosimetry for use with alpha-particle emitters. In addition to the absorbed dose (average specific energy) to the targets (cell nuclei), this system gives the spread (standard deviation) in values of this specific energy received by individual targets. It also gives the fraction of targets receiving zero (or any number of) hits. In this paper, input quantities are presented for alpha-particle energies and cell and nuclear sizes appropriate for the radionuclides being investigated. The quantities include S values for the usual determination of the absorbed dose along with the microdosimetric quantities, and <(z1)2>, the average and average square, respectively, of the single-hit specific energy. Using analytical procedures described previously [Med. Phys. 19, 1385-1393 (1992)], the single-hit distributions of specific energy are determined for the given alpha-particle energies, source locations, and target sizes. From these distributions, the values for the input quantities are calculated. Sources considered are (1) those located inside and on the surface of the target cell and an unbounded source in the medium external to the cell; (2) those distributed uniformly on either side of a plane boundary or on the surface of the plane with a spherical target at various distances from the plane; and (3) those located either inside or on the surface of a spherical boundary centered externally to the target. Examples show how the input quantities are used to provide the spread in specific-energy values and the probability of any number of hits for nuclei of cells exposed to these sources. Thus a complete micro-dosimetric analysis involving the calculation of multi-hit specific energy distributions is not necessary to provide this information. Such information may be useful in interpreting the biological response due to alpha-particle emitters.

Alpha Particles↗

PubMed1995

The quality of DNA double-strand breaks: a Monte Carlo simulation of the end-structure of strand breaks produced by protons and alpha particles.

The quality of DNA damage induced by protons and alpha-particles of various linear energy transfer (LET) was studied. The aim was to single out specific lesions in the DNA molecule that might lead to biological endpoints such as inactivation. A DNA model coupled with a track structure code (MOCA-15) were used to simulate the lesions induced on the two helixes. Four categories of DNA breaks were considered: single-strand breaks (ssb), blunt-ended double-strand breaks (dsb, with no or few overlapping bases), sticky-ended double-strand breaks (with cohesive free ends of many bases), and deletions (complex lesions which involve at least two dsb within a small number of base pairs). Calculations were carried out assuming various sets of parameters characterizing the production of these different DNA breaks. No large variations in the yields of ssb and blunt- or sticky-ended dsb were found in the LET range between 10 and 200 keV/mu m. On the other hand, the yield of deletions increases up to about 100 keV/mu m and seems to reach a plateau at higher LET values. In the LET interval from 30 to 60 keV/mu m, protons proved to be more efficient than alpha-particles in inducing deletions. The induction of these complex lesions is thus dependent not simply on LET but also on the characteristics of the track structure. Comparison with RBE values for cell killing shows that this special class of dsb might play an important role in radiation-induced cell inactivation.

Alpha Particles↗

PubMed1976

Rapid appearance of transient secondary adrenocortical insufficiency after alpha-particle radiation therapy for Cushing's disease.

A 17-year-old women received 12,000 rads of alpha-particle radiation for the treatment of Cushing's disease. One day after the completion of therapy, the patient developed nausea, vomiting, headache, and postural hypotension. Laboratory evaluation demonstrated a marked fall of the previously elevated urinary 17-hydroxycorticosteroids (17-OHCS) and undetectable plasma cortisols. The urinary 17-OHCS transiently returned to supranormal levels but over a 2 1/2-week period decreased and then remained low. The patient also demonstrated a subnormal urinary aldosterone excretion in relation to plasma renin activity (PRA) during 10 mEq/24 h sodium restriction. The remainder of the endocrine evaluation was normal, suggesting that pituitary function otherwise remained intact. One and one-half years after alpha-particle therapy, the patients's urinary 17-OHCS were normal and responded normally to metyrapone. The relationship between urinary aldosterone excretion and PRA also was normal. It is postulated that there was an infarction of an ACTH secreting pituitary tumor leaving the remainder of the pituitary intact. Achronically elevated circulating level of ACTH with sudden loss of ACTH secretion appeared to have been responsible for the initial low urinary aldosterone as well as the low urinary 17-OHCS. This is the first reported case of a presumed pituitary tumor infarction in association with alpha-particle pituitary radiation.

17-Hydroxycorticosteroids↗

PubMed2002

Absorbed dose delivered by alpha particles calculated in cylindrical geometry.

The present work aims to develop a semi-analytical method to calculate the absorbed dose delivered by alpha particles in a cylindrical geometry. This method will be employed to reproduce the dose conversion coefficients or absorbed fraction of alpha particles in sensitive cells of the tracheobronchial tree obtained by NRC and ICRP, respectively. The difference caused by using water stopping power and tissue stopping power will also be investigated. Linear stopping powers for alpha particles in tissue and air were calculated, and the dependences of stopping powers on the traveled distance were established. A geometry model is set up for our calculations, and two different cases have been considered, namely the near-wall and far-wall cases. The total energy imparted to a unit-diameter sphere around a point is shown to be obtainable from a triple integral, which can be solved numerically. The absorbed dose is found to be independent of the diameter of the sphere being considered and additional assumptions about its diameter were not needed. The results obtained are in good agreement with those obtained previously by NRC and ICRP66. Using the semi-analytical method developed in the present work, the dose conversion coefficients or absorbed fraction previously obtained by NRC and ICRP, respectively, have been satisfactorily reproduced. Using the tissue stopping power instead of the water stopping power can slightly lower the values for dose conversion coefficients in the bronchial region.

Absorption↗

PubMed2000

Modeling energy deposition and cellular radiation effects in human bronchial epithelium by radon progeny alpha particles.

Energy deposition and cellular radiation effects arising from the interaction of single 218Po and 214Po alpha particles with basal and secretory cell nuclei were simulated for different target cell depths in the bronchial epithelium of human airway generations 2, 4, 6, and 10. To relate the random chord lengths of alpha particle tracks through spherical cell nuclei to the resulting biological endpoints, probabilities per unit track length for different cellular radiation effects as functions of LET were derived from in vitro experiments. The radiobiological data employed in the present study were inactivation and mutation (mutant frequency at the HPRT gene) in V79 Chinese hamster cells and inactivation and transformation in C3H 10T1/2 cells. Based on computed LET spectra and relative frequencies of target cells, probabilities for transformation, mutation, and cell killing in basal and secretory cells were computed for a lifetime exposure of 20 WLM. While predicted transformation probabilities were about two orders of magnitude higher than mutation probabilities, they were still about two orders of magnitude lower than inactivation probabilities. Furthermore transformation probabilities for basal cells are generally higher than those for secretory cells, and 214Po alpha particles are primarily responsible for transformations in bronchial target cells.

Animals↗

PubMed2003

Alpha-particle production in the reaction 6Li+28Si at near-barrier energies.

The production of alpha particles in the 6Li+28Si reaction was studied at near-barrier energies. Angular distributions were performed at four bombarding energies, namely, 7.5, 9, 11, and 13 MeV. The distributions were characterized by a Gaussian shape, which was integrated in order to obtain alpha-particle cross sections. Our results were compared with previous data of 6Li scattering on various heavier targets and found to exhibit a universal behavior. Present continuum-discretized-coupled-channel calculations support the obtained data. The consequences of the systematic behavior of the alpha-particle production on the unusual behavior of the imaginary potential observed previously in elastic scattering of weakly bound systems is discussed.

Journal Article↗

PubMed1998

Theoretical treatment of human haemopoietic stem cell survival following irradiation by alpha particles.

PURPOSE: To calculate survival of human haemopoietic stem cells irradiated by alpha particles from 149Tb (initial energy 3.97 MeV) and 211At (average initial energy 6.87 MeV). METHODS: Following as closely as possible radiobiological data, Monte Carlo methods were used to calculate passages of alpha particles (originating in three geometries) through the nuclei of haemopoietic stem cells. Survival of stem cell populations was calculated from the probability of surviving each passage (a function of LET). RESULTS: For decays targeted to the surface of individual cells 37% survival was found at 1.3 passages per nucleus for 149Tb and 6.5 for 211At/Po decays. For decays distributed in a large volume the D0 doses were 0.81 and 0.87 for 149Tb and 211At respectively. When 36% of the marrow is occupied by fat cells alphas from 149Tb are more effective with a D0 of 0.68Gy compared to 0.82Gy for the 211At/Po combination. CONCLUSIONS: When the isotopes are targeted to the cell, in terms of passages, 149Tb is five times more effective at cell killing than 211At, which when expressed in terms of dose, increases to a factor of 9. When the isotopes are broadly distributed (such as in marrow or in vitro) the differences are considerably reduced.

Alpha Particles↗

PubMed1997

Cumulative genetic damage in hematopoietic stem cells in a patient with a 40-year exposure to alpha particles emitted by thorium dioxide.

Thorotrast, a colloidal suspension of the long-lived radionuclide, thorium-232, was widely used as a radiographic contrast medium for several decades. Due to the poor excretion of the sol, however, Thorotrast would deposit in the liver, bone marrow and other tissue, and patients would receive alpha-particle irradiation for life. To gauge the cumulative genetic damage to hematopoietic stem cells due to chronic exposure to alpha particles, we conducted a multi-end-point evaluation in a 72-year-old man who had been administered a 32-ml bolus of Thorotrast during cerebral angiography performed over 40 years ago in 1950. Peripheral T lymphocytes were cultured to quantify the frequencies and cellular distributions of asymmetrical and symmetrical types of chromosome aberrations in first-division metaphases and micronuclei in cytokinesis-arrested interphase II cells. Aberrations were scored using classical chromosome group analysis methods and chromosome painting techniques. Assays of glycophorin-A (GPA) mutations in red blood cells were also performed to obtain a relative measurement of damage sustained by the erythroid stem cell population. Results revealed that approximately 30% of the lymphocytes in this patient contained one or more chromosome aberrations, the majority of which were of the "stable" type. About one-third of the lymphocytes with chromosome damage carried multiple aberrations, suggesting that significant numbers of stem cells survive exposures to alpha-particle radiation that induce complex genomic alterations. Increased frequencies of GPA mutations were observed, demonstrating that genomic damage is also induced in erythroid progenitors. The numbers of micronuclei in lymphocytes were only moderately increased compared to expected values for persons of comparable age, and thus this end point was not useful for quantifying exposure level. Despite the relatively severe burden of somatic cell damage induced by 40 years of internal alpha-particle irradiation, the patient remains surprisingly free of any serious illness.

Alpha Particles↗

PubMed1994

Plutonium-catalyzed oxidative DNA damage in the absence of significant alpha-particle decay.

Plutonium is considered to be a carcinogen because it emits alpha particles that may result in the irradiation of stem cell population. In the present study we show that plutonium can also catalyze reactions that induce hydroxyl radicals in the absence of significant alpha-particle irradiation. Using the low specific activity isotope, 242Pu, experiments were performed under conditions in which chemical generation of hydroxyl radicals was expected to exceed the radiolytic generation by one hundred thousand-fold. The results showed that markers of oxidative DNA base damage, thymine glycol and 8-oxoguanine could be induced from plutonium-catalyzed reactions of hydrogen peroxide and ascorbate similarly to those occurring in the presence of iron catalysts. Plutonium-242, as a neutralized nitrate in phosphate buffer, was 4.8-fold more efficient than iron at catalyzing the oxidation of ascorbate at pH 7. The results suggest that plutonium complexes could participate in reactions at pH 7 that induce oxidative stress--a significant tumor-promoting factor in generally accepted models of carcinogenesis.

Alpha Particles↗

PubMed2003

Microdosimetric analysis of alpha-particle-emitting targeted radiotherapeutics using histological images.

UNLABELLED: The purpose of this study was to evaluate the therapeutic efficacy and limitations of alpha-particle-emitting radiolabeled compounds by means of 2-dimensional histological images and distribution of activity on a microscopic level. METHODS: A microdosimetric approach based on histological images is used to analyze the therapeutic effectiveness of alpha-particle-emitting (211)At and (213)Bi conjugated to 201B monoclonal antibody (mAb), which is reactive with murine lung blood vessels for the treatment of EMT-6 lung tumor colonies in nude mice. Autoradiography images were used to define the tissue morphology and activity distribution within lung tissues. Two animal groups were studied: Group A consisted of animals bearing small tumors (<130 micro m) and group B consisted of larger tumors (<600 micro m). Probability density functions (pdf) described the variability in average absorbed dose and survival probability among normal and tumor target cells and, in turn, were used to assess the survival fraction of tumor and normal tissue. RESULTS: The average absorbed dose to tumor cells per unit cumulated activity concentration for animals in group A was 1.10 x 10(-3) and 1.37 x 10(-3) Gy g MBq(-1) s(-1) for (211)At and (213)Bi, respectively, and for animals in group B was 3.8 x 10(-4) and 5.6 x 10(-4) Gy g MBq(-1) s(-1) for (211)At and (213)Bi, respectively. The fraction of tumor cells that received a zero absorbed dose for animals in group A was 0.04% for (213)Bi and 0.2% for (211)At and for animals in group B was 25% for (213)Bi and 31% for (211)At. Both (213)Bi- and (211)At-labeled 201B mAb were effective therapies for animals with small tumors, where predicted therapeutic effectiveness was consistent with experimental findings; however, they were ineffective for animals with larger tumors. CONCLUSION: Microdosimetric methods based on knowledge of tissue morphology and activity distribution on a small-scale level can be a useful tool for evaluating a priori the therapeutic efficacy and limitations of targeted alpha-particle endoradiotherapeutic strategies.

Alpha Particles↗

PubMed1992

Cellular kinetics, dosimetry, and radiobiology of alpha-particle radioimmunotherapy: induction of apoptosis.

Though clinical results for radioimmunoconjugate therapy of most common epithelial tumors have been disappointing, dramatic responses have been observed repeatedly in the treatment of high- and low-grade malignant lymphomas. This high clinical responsiveness after radioimmunoconjugate therapy sometimes appears to be out of proportion to the calculated radiation dose absorbed by the lymphoma tissue. Here we describe some key aspects of the kinetics, dosimetry, and cellular radiobiology of murine lymphoma cells exposed to 212Bi-radiolabeled alpha-particle-emitting immunoconjugates specific for the differentiation antigen Thy 1.2. Approximately 25 cell-bound alpha-particle-emitting immunoconjugates per target cell were required to reduce clonogenic survival by 90% (the radiobiological D10). Serial kinetic analyses of the antibody and radioisotope components of the immunoconjugates revealed significant levels of dechelation and up to 7.5% cellular internalization of the isotope. Cellular radiation dosimetry performed by Monte Carlo computer simulation of alpha-particle energy deposition patterns based on the observed radiopharmacokinetics showed that the D10 resulted from approximately four alpha-particle traversals through the nucleus, corresponding to an absorbed radiation dose of approximately 0.95 Gy to the cell nucleus. Electron micrographs and DNA gel studies of murine lymphoma cells undergoing radioimmunoconjugate therapy in vivo and in vitro demonstrated bizarre blebbing patterns, condensation of chromosomal material, and internucleosomal DNA fragmentation patterns characteristic of programmed cell death (apoptosis). We conjecture that the efficacy of radioimmunoconjugates against responsive cell types may be the result of passive DNA damage by ionizing radiation and the initiation of apoptosis in response to radioimmunotherapy.

Alpha Particles↗

PubMed1999

Unexpected sensitivity to the induction of mutations by very low doses of alpha-particle radiation: evidence for a bystander effect.

We examined the induction of HPRT mutations in CHO cells exposed to low fluences of (238)Pu alpha particles from a specially constructed irradiator. The dose-response relationship was linear over the dose range of 5 cGy-1.2 Gy. However, unexpected sensitivity, leading to a significantly higher frequency of mutations than would be predicted by a back extrapolation from the data for higher doses, was observed in the dose range below 5 cGy, where the mean number of alpha-particle traversals per nucleus was significantly less than one (0.05-0.3). The frequency of mutations induced by a single alpha particle traversing the nucleus of a cell was increased nearly fivefold at the lowest fluence studied. The data are consistent with the conclusion that the enhanced efficiency of each nuclear traversal at low particle fluences is the result of mutations arising in nonirradiated, bystander cells.

Alpha Particles↗

PubMed2003

Transmissible and nontransmissible complex chromosome aberrations characterized by three-color and mFISH define a biomarker of exposure to high-LET alpha particles.

Insertions have been proposed as potential stable biomarkers of chronic high-LET radiation exposure. To examine this in vitro, we irradiated human peripheral blood lymphocytes in G(0) with either 50 cGy (238)Pu alpha particles (LET 121.4 keV/microm) or 3 Gy 250 kV X rays and stimulated their long-term culture up to approximately 22 population doublings postirradiation. Mitotic cells were harvested at regular intervals throughout this culture period and were assayed for chromosome aberrations using the techniques of three-color and 24-color mFISH. We observed the stable persistence of transmissible-type complex rearrangements, all involving at least one insertion. This supports the hypothesis that insertions are relevant indicators of exposure to high-LET radiation. However, one practical caveat of insertions being effective biomarkers is that their frequency is low due to the complexity and cell lethality of the majority of alpha-particle-induced complexes. Therefore, we propose a "profile of damage" that relies on the presence of insertions, a low frequency of stable simple reciprocal translocations (2B), and, significantly, the complexity of the damage initially induced. We suggest that the complexity of first- and second-division alpha-particle-induced nontransmissible complex aberrations reflects the structure of the alpha-particle track and as a consequence adds radiation-quality specificity to the biomarker, increasing the signal:noise ratio of the characteristic 2B:insertion ratio.

Chromosome Aberrations↗

PubMed1983

Lipid peroxidation by ultraviolet light and high energy alpha particles from a cyclotron.

High energy alpha-particles (approximately 16 MeV) and 254 nm ultraviolet light produced dose dependent linear increase of lipid hydroperoxides in the dried thin film state. For both types of radiation, an inverse dose-rate effect, i.e., a protracted radiation dose was more effective than a shorter, more intense one of larger size, was observed. Ultraviolet light (254 nm) produced higher yields of hydroperoxides in the aqueous liposomal suspension of lipid than in its dried thin film state.

Alpha Particles↗

PubMed1978

Energy dependence of W for alpha particles in N2, CO2, CH4, Ar, H2 and Rossi-type tissue-equivalent gases.

Average energy required to form an ion pair (W) was determined in N2, CO2, CH4, Ar, H2 and Rossi-type tissue-equivalent gas. Alpha particles from a 241Am source were used. W was determined at alpha energies of 5.37, 3.12, 1.08 and 0.46 MeV. The ratio of total ionisation produced (for fixed alpha particle energy) in experimental gas to that produced in argon was measured. This ratio was then multiplied by the previously determined W value for argon gas (26.29 eV per ion pair) to yield W for various experimental gases. Energy of the 241Am alpha particles was degraded by using air as an absorbing material. Empirical relations W = alpha + betaE-1/2 and W = alpha1 + beta1E-1 were fitted to the experimental data. Both functions fit reasonably well in the range 0.4--5.37 MeV. Below about 0.4 MeV the first function provides a better fit to the data of Boring et al. (1965).

Alpha Particles↗