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PubMed2001

Lymphocyte chromosomal aberrations and their complexity induced in vitro by plutonium-239 alpha-particles and detected by FISH.

G0 human lymphocytes were exposed in vitro to plutonium-239 alpha-particles, with doses ranging from 0 to 1.62 Gy, to provide a dose response curve and to compare complex rearrangements produced by high LET radiation with low LET data from previous work. Metaphase chromosomes 1 and 2 were painted using fluorescence in situ hybridization (FISH) whole chromosome probes. All unstable and stable aberrations involving the painted chromosomes were scored. The whole genome corrected alpha-coefficient for dicentrics was 0.244 +/- 0.023 and for total translocations 0.346 +/- 0.032, when considering simple and complex exchanges. The ratio of bicoloured total translocations to bicoloured dicentrics was 1.21 +/- 0.15 and the ratio of 2-way to 1-way translocations was 1.73 +/- 0.27 for apparently simple exchanges only. A correlation was noted between the distributions of dicentrics and translocations and this applied even when the complex rearrangements were removed. 20% of the observed rearrangements were complex and this observation was independent of dose. Qualitatively, following irradiation with alpha-particles the complex rearrangements observed were of a greater complexity than seen after X- or gamma-rays. Using the Savage and Simpson system to classify the complex rearrangements, the higher order complexes were found to be the most common type observed. However the insertion type increased while the 2F + 2G types decreased when complex rearrangements induced by alpha-particles were compared to those formed after X- or gamma-irradiation.

Alpha Particles↗

PubMed1987

Cancer incidence and lifespan vs. alpha-particle dose in beagles.

Young adult beagles were injected with graded activities of 239Pu, 241Am, 228Th, 228Ra or 226Ra and observed throughout their lifespans. The vast majority of the dose was from alpha particles. The lifetime incidence of bone sarcoma increased with average skeletal dose, more or less linearly up to high incidence for 239Pu, 241Am, 228Th and 226Ra, but sigmoid fashion for 228Ra. Based on average skeletal dose, the toxicity of the emitters relative to 226Ra = 1.0 was 239Pu = 16.6 +/- 4.5, 241Am = 5.4 +/- 1.6, 228Th = 8.5 +/- 2.3 and 228Ra = 2.0 +/- 0.5. At the lowest doses, the average lifespans were 97% +/- 3% of that in the controls. If beneficial effects occurred, they may have been overwhelmed by the destructiveness of the densely ionizing alpha particles. A cell nucleus 5 micron in diameter receives a mean dose of about 1 Gy (100 rad) when traversed by a single alpha particle. We found no evidence that alpha-particle doses suppressed cancer or lengthened lifespan in beagles.

Alpha Particles↗

PubMed1990

Alpha-particles induce preneoplastic transformation of rat tracheal epithelial cells in culture.

To characterize the potential role of high-l.e.t. radiation in respiratory carcinogenesis, the cytotoxic and transforming potency of 5.5 Me V alpha-particles from electroplated sources of 238Pu were determined using primary cultures of rat tracheal epithelial cells. The alpha-particle response was compared to the effects of 280 kVp X-rays and of the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine. Increasing the alpha-particle dose caused an exponential decrease in survival with a D37 of 1.6 Gy. X-rays also caused a dose-dependent decrease in survival (D37 = 3.6 Gy) but the survival curve had a significant shoulder. The RBE for cell killing by alpha-particles versus X-rays varied with dose, and ranged between 4 and 1.5 for alpha doses in the range 0.2-4 Gy. At equally toxic doses (relative survival 0.18-0.2), all three agents induced similar frequencies of preneoplastic transformation. For preneoplastic transformation induced by doses of alpha- and X-radiations giving 80 per cent toxicity, an alpha RBE of 2.4 was derived. The similar RBEs for cell killing and for preneoplastic transformation suggest an association between the type or degree of radiation-induced damage responsible for both cell killing and cell transformation.

Alpha Particles↗

PubMedDate not supplied

[The RBE of 239Pu alpha particles for radiosensitive mutant yeast irradiated at a logarithmic growth stage].

The relative biological efficiency (RBE) of alpha particles for wild-type yeast cells and radiosensitive mutants exposed in stationary and logarithmic stages of growth was compared. A correlation between the RBE of densely ionizing radiation and cell repair capacity was supported for plateau-phase cultures. It was shown for the first time that RBE of alpha particles for cells exposed in logarithmic stage was less than the RBE for stationary cells for all strains studied. For the most mutant cells RBE of alpha particle was closed to unity, i.e. cell radiosensitivity was almost identical for sparsely and densely ionizing radiation. Possible reasons for the observed radiation responses are discussed.

Alpha Particles↗

PubMed2004

Calculations of cellular microdosimetry parameters for alpha particles and electrons.

The cellular microdosimetry parameters including the cellular S-value and the single-event specific energy distribution for alpha particles and electrons are important in radiation dosimetry and biology. These parameters may be used to determine the relative biological effectiveness of radiations in the boron neutron capture therapy. In the present work, such parameters were calculated for different source to target region combinations, i.e. cell surface, cytoplasm, nucleus and cell. Calculations were made using a semi-analytical model that simulated the emission of alpha particles or electrons by the Monte Carlo method and calculated the energy imparted to the target volume by the analytical method. Delta particle equilibrium and partial delta particle equilibrium were applied to alpha particles and electrons, respectively. Range-energy relations were employed to determine the incident and emerging energies of the primary particles. For electrons, the fraction in the energy loss resulting from the generation of bremsstrahlung and high-energy secondary electrons was estimated. The energy loss straggling of electrons entering and leaving a target volume was also estimated. Calculated cellular S-values were compared to corresponding data of the MIRD Committee. Calculated single-event specific energy distributions were also compared to results calculated using the Penelope code.

Alpha Particles↗

PubMed1993

The feasibility of 225Ac as a source of alpha-particles in radioimmunotherapy.

This paper proposes the utilization of 225Ac for the alpha-radioimmunotherapy of cancer. The isotope decays with a radioactive half-life of 10 days into a cascade of short-lived alpha- and beta-emitting isotopes. In addition, when indicated by the pharmacokinetic requirements of particular clinical applications, 213Bi, with a radioactive half-life of 47 min, can be chosen as an alternative source of alpha-particles in radioimmunotherapy. This isotope is the last alpha emitter in the 225Ac decay-cascade and can be extracted from a 225Ac source at the bedside of the patient. 225Ac can quasi ad infinitum be obtained from one of its precursors, 229Th, which can be made available by various means. The indications for the use of alpha-particles as an alternative to more traditional classes of radiation are derived from the particle-kinetic characteristics and the radioactive half-life of their source isotope, as well as from the properties of the target-selective carrier moiety for the source isotope. It may be expected that useful applications, complementary to and/or in conjunction with other means of therapy will be identified.

Actinium↗

PubMed1992

Direct comparison between protons and alpha-particles of the same LET: I. Irradiation methods and inactivation of asynchronous V79, HeLa and C3H 10T1/2 cells.

A direct comparison was carried out of the biological effectiveness of protons and alpha-particles of the same linear energy transfer (LET) under identical conditions with a variety of in vitro biological systems. Monolayers of mammalian cells were irradiated with accelerated beams of protons (1.2 and 1.4 MeV) and alpha-particles (30 and 35 MeV) corresponding to LETs of 23 and 20 keV microns-1 for each particle type. For V79-4 cells it was observed that the linear term of the dose-response for cell inactivation by protons was significantly greater than that for alpha-particles of the same LET. For HeLa and HeLa S3 cells, also, the linear term appeared to be greater for protons, but this was not observed with more limited data for C3H 10T1/2 cells. The result for V79 cells is in agreement with the report of Belli et al. (1989) who observed that the biological effectiveness of protons rose sharply between 17 and 30 keV microns-1 in strong contrast to alpha-particles which reached a peak effectiveness at greater than 100 keV microns-1. These results place new constraints on the biologically relevant features of the microscopic structure of radiation tracks, and have implications for the mechanistic and practical comparison between radiations.

Alpha Particles↗

PubMed2002

Measurement of alpha particle energy using windowless electret ion chambers.

Electret ion chambers are inexpensive, lightweight, robust, commercially available, passive, charge-integrating devices for accurate measurement of different ionizing radiations. In an earlier work a chamber of dimensions larger than the range of alpha particles having aluminized Mylar windows of different thickness was used for measurement of alpha radiation. Correlation between electret mid-point voltage, alpha particle energy, and response was developed and it was shown that this chamber could be used for estimating the effective energy of an unknown alpha source. In the present study, the electret ion chamber is used in the windowless mode so that the alpha particles dissipate their entire energy inside the volume, and the alpha particle energy is determined from the first principles. This requires that alpha disintegration rate be accurately known or measured by an alternate method. The measured energies were within 1 to 4% of the true values for different sources (230Th, 237Np, 239Pu, 241Am, and 224Cm). This method finds application in quantitative determination of alpha energy absorbed in thin membrane and, hence, the absorbed dose.

Americium↗

PubMed1994

Alpha-particle-induced p53 protein expression in a rat lung epithelial cell strain.

Other investigators have shown that both sparsely ionizing and UV radiation cause cell cycle arrest that is associated with increased expression of wild-type p53 protein. The effect of exposure to alpha-particles from 238Pu on the induction of the p53 protein has now been examined in cultured lung epithelial cells derived from male F344 rats. The number of cells having increased levels of p53 protein was determined by flow cytometry after the cells had been stained with a monoclonal antibody to p53. alpha-Particle irradiation caused a dose-dependent increase in p53 protein levels detectable at doses as low as 0.6 cGy, with no evidence of a threshold. An increase in p53 protein also occurred in X-irradiated cells. However, no increase was seen in cells exposed to less than 10 cGy of X-rays, indicating the existence of a relatively higher DNA damage threshold for sparsely ionizing radiation. In addition, more cells exposed to low doses of alpha radiation had increased p53 protein levels than would be predicted based on the number of nuclei expected to be traversed by an alpha-particle, suggesting that alpha-particles cause genetic damage by mechanisms in addition to direct interactions with DNA.

Alpha Particles↗

PubMed1998

Deletion-pattern analysis of alpha-particle and X-ray induced mutations at the HPRT locus of V79 Chinese hamster cells.

To investigate the mutagenic mechanisms of low-energy alpha particles V79 Chinese hamster cells were irradiated with 241Am-alpha particles (mean LET of 112 keV/micron). Parallel experiments were performed using 300 kV X-rays. Cell inactivation and mutation induction cross sections were measured. At approximately 20%--survival level, DNA deletions were analysed at the HPRT locus by multiplex-PCR-analysis of all nine exons of 47 alpha-irradiated and 36 background mutants. 92 HPRT- mutants isolated after 300 kV-X-irradiation were analysed similarly for comparison, along with 15 corresponding background mutants. The resulting mutant deletion-pattern distributions were corrected for background mutations. alpha Particles induced a larger fraction of deletions than X-rays. Furthermore, non-contiguous partial deletions were present among the alpha-induced mutants, a type not found after X-irradiation.

Alpha Particles↗

PubMed2001

Response of LNCaP spheroids after treatment with an alpha-particle emitter (213Bi)-labeled anti-prostate-specific membrane antigen antibody (J591).

A theoretical drawback to alpha-particle therapy with 213Bi is the short range of the particle track coupled with the short half-life of the radionuclide, thereby potentially limiting effective cytotoxicity to rapidly accessible, disseminated individual tumor cells (e.g., as in leukemia). In this work, a prostate carcinoma spheroid model was used to evaluate the feasibility of targeting micrometastatic clusters of tumor cells using 213Bi-labeled anti-prostate-specific membrane antigen (PSMA) antibody, J591. In prostate cancer, vascular dissemination of tumor cells or tumor cell clusters to the marrow constitutes an important step in the progression of this disease to widespread skeletal involvement, an incurable state. Such prevascularized clusters are ideal targets for radiolabeled antibodies because the barriers to antibody penetration that are associated with the capillary basal lamina have not yet formed. Beta- and gamma-emitting radionuclides such as 131I, which are widely used in radioimmunotherapy, are not expected to be effective when targeting single cells or small cell clusters. This is because the range of the emissions is one to two orders of magnitude greater than the target size, and the energy deposited per traversal is insufficient to produce any significant radiobiological effect. Spheroids of the prostate cancer cell line, LNCaP-LN3, were used as a model of prevascularized micrometastases; their response to an anti-PSMA antibody, J591, radiolabeled with the alpha-particle emitter 213Bi (T(1/2), 45.6 min.) has been measured. The time course of spheroid volume reductions was found to be sensitive to the initial spheroid volume. J591 labeled with 0.9 MBq/ml 213Bi resulted in a 3-log reduction in spheroid volume on day 33, relative to control, for spheroids with an initial diameter of 130 microm; 1.8 MBq/ml were required to achieve a similar response for spheroids with an initial diameter of 180 microm. Equivalent spheroid responses were observed after 12 Gy of acute external beam photon irradiation. Monte Carlo-based microdosimetric analyses of the 213Bi decay distribution in individual spheroids of 130-microm diameter yielded an average alpha-particle dose of 3.7 Gy to the spheroids, resulting in a relative biological effectiveness factor of 3.2 over photon irradiation. The activity concentrations used in the experiments were clinically relevant, and this work supports the possibility of using 213Bi-labeled antibodies not only for disseminated single tumor cells, as found in patients with leukemia, but also for micrometastatic tumor deposits up to 180 microm in diameter (1200 cells).

Alpha Particles↗

PubMed1999

Temporal change in microdosimetry to bone marrow and stromal progenitor cells from alpha-particle-emitting radionuclides incorporated in bone.

The microdistributions of the alpha-particle-emitting bone surface-seeking radionuclides (239)Pu, (241)Am and (233)U in the mouse femoral shaft have been studied using computer-based image analysis of neutron-induced and alpha-particle track autoradiographs, prepared from femora of CBA/H mice which had been injected with 40 kBq kg(-1) of radionuclide (as citrate solution) at times from 1 to 448 days previously. Employing dosimetric methods, radiation dose rates and cumulative radiation doses to regions of the bone marrow thought to contain hemopoietic and stromal progenitor cells susceptible to neoplastic transformation to leukemia and osteosarcomas have been calculated. It has been shown that the three radionuclides differ in their relative deposition on the bone surfaces, and that patterns of changing redistribution with time are also varied. For stromal progenitor cells, which are thought to be targets for induction of osteosarcoma and are found in proximity to the bone surfaces, cumulative doses showed the trend (239)Pu > (241)Am > (233)U, correlating well with incidences of osteosarcoma observed in mice. Cumulative doses to the primitive hemopoietic stem cells, concentrated in the central marrow and thought to be susceptible to neoplastic transformation to myeloid leukemia, were considerably lower and also showed the trend plutonium > americium > uranium.

Alpha Particles↗

PubMedDate not supplied

Study of alpha-particle emission probabilities and energies in the decay of 240Pu.

In the frame of EUROMET Project No 325 "Analysis of Plutonium Alpha-Particle Spectra", the isotopic composition of a 238, 239, 240Pu mixture was measured by mass spectrometry and by high-resolution alpha-particle spectrometry. The latter revealed a discrepancy with published data of the alpha-particle emission probabilities (Palpha) and the energies (Ealpha) of the two major peaks of 240Pu. New values have been derived: Palpha1 = 0.7256 (6), Palpha2 = 0.2735 (7) and Ealpha1 = 5168.54 (14)keV, Ealpha2 = 5124.10 (15)keV, relative to reference peaks of 238Pu and 239Pu.

Alpha Particles↗

PubMed1988

Alpha-particle-induced cancer in humans.

Updated information is given on alpha-particle-induced cancer in persons internally exposed to 222Rn progeny, Thorotrast, long-lived 226Ra and 228Ra, and short-lived 224Ra. The lung cancer risk to persons breathing 222Rn progeny in the indoor air of offices, schools, and homes is of increasing concern. About half of the recent deaths among the German Thorotrast patients have been from liver cancer. Animal studies indicate that the liver cancer risk from Thorotrast is mainly from its radioactivity and that the risk coefficient for the Thorotrast patients can be used provisionally for other alpha emitters in the human liver. Six skeletal cancers have occurred in persons with average skeletal doses between 0.85 and 11.8 Gy from 226Ra and 228Ra. In the low-dose German 224Ra patients, two skeletal sarcomas have occurred at about 0.7 Gy compared to about six cases predicted by results from 224Ra patients at higher doses. The minimal appearance time for radiation-induced bone sarcomas in humans is about 4 y. Following brief irradiation, the vast majority of induced bone sarcomas are expressed by about 30 y. Recent evidence against the "practical threshold" hypothesis is given. With the downward revision of neutron doses to the atomic-bomb survivors, the follow-up of persons exposed to alpha particles may be the best opportunity to evaluate directly the effects of high LET radiation on humans.

Alpha Particles↗

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↗

PubMed2004

Effect of americium-241 alpha-particles on the dose-response of chromosome aberrations in human lymphocytes analysed by fluorescence in situ hybridization.

PURPOSE: To evaluate by the fluorescent in-situ hybridization (FISH) technique the dose-response and intercellular distribution of alpha-particle-induced chromosome aberrations. In particular, the validity of using the yield of characteristic types of chromosome abnormalities in stable cells as quantitative indicators for retrospective dose reconstruction has been evaluated. MATERIAL AND METHODS: Monolayers of human peripheral lymphocytes were exposed at doses from 0.02 to 1 Gy to alpha-particles emitted from a source of americium-241. The most probable energy of the alpha-particles entering the cells was 2.7 MeV. FISH painting was performed using DNA probes for chromosomes 2, 4 and 8 in combination with a pan-centromeric probe. In complete first-division cells, identified by harlequin staining, aberrations involving painted target chromosomal material were recorded as well as aberrations involving only unpainted chromosomal material. RESULTS: In total, the percentage of complex aberrations was about 35% and no dose dependence was observed. When complex-type exchanges were reduced to simple base types, the different cell distributions were clearly over-dispersed, and the linear coefficients of the dose-effect curves for translocations were significantly higher than for dicentrics. For past dose reconstruction, only a few complex aberrations were in stable cells. The linear coefficient obtained for transmissible aberrations in stable cells was more than seven times lower than that obtained in all analysed cells, i.e. including unstable cells. CONCLUSION: FISH-based analysis of complex rearrangements allows discrimination between partial-body exposures to low-linear energy transfer radiation and high-linear energy transfer exposures. In assessing past or chronic exposure to alpha-particles, the use of a dose-effect curve obtained by FISH-based translocation data, which had not excluded data determined in unstable cells, would underestimate the dose. Insertions are ineffective biomarkers because their frequency is too low.

Adult↗

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↗