The passage of proteins and particles alpha-cross the surface of cells.
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Alpha Particles↗
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Radioimmunotherapy of peritoneal human colon cancer xenografts with site-specifically modified 212Bi-labeled antibody.
212Bi is a radioisotope that emits highly cytotoxic alpha-particles. alpha-particles have a high linear energy transfer over a short path length. These properties and the 1-h half-life make this isotope suitable for radioimmunotherapy of peritoneal tumors. Therefore, we wanted to test whether monoclonal antibodies labeled with 212Bi would be effective in treating such tumors. We conjugated the antibody B72.3, which is reactive with many human adenocarcinomas, to the chelator linker glycyltyrosyl-lysyl-N-epsilon-diethylenetriaminepentaacetic acid, by reductive amination to the carbohydrate residues of the antibody (J. Rodwell, et al. Proc. Natl. Acad. Sci. USA, 83: 2632-2636, 1986). Athymic nude mice were injected i.p. with LS174T cells, a human colon cancer cell line. Seven to 13 days later the mice were treated with the 212Bi-labeled antibody. We treated the mice using single doses of 180-450 microCi or multiple doses of 80-180 microCi on consecutive days. Dissections were performed 9-16 days after the end of treatment. Both the single and multiple doses resulted in a decrease in tumor burden when compared to tumor from mice receiving unlabeled antibody. Mice in the optimum group showed tumor reductions of greater than 90%. Treatment with a 212Bi-labeled irrelevant antibody was significantly less effective than that with labeled B72.3 antibody. Survival studies showed that mice receiving the labeled antibody had a prolonged survival when compared to control mice.
Animals↗
Therapeutic radionuclides: production and decay property considerations.
The development of effective therapeutic radiopharmaceuticals requires careful consideration in the selection of the radionuclide. The in vivo targeting and clearance properties of the carrier molecule must be balanced with the decay properties of the attached radionuclide. Radionuclides for therapeutic applications fall into three general categories: beta-particle emitters, alpha-particle emitters, and Auger and Coster-Kronig-electron emitters following electron capture. Alpha particles and Auger electrons deposit their energy over short distances with a high LET that limits the ability of cells to repair damage to DNA. Despite their high levels of cytotoxicity, the relatively short range of alpha particles requires binding of the carrier molecule to most cancer cells within a tumor in order to be effective. Because of the extremely short range of Auger electrons, the radionuclide must be carried directly into the nucleus to elicit high radiotoxicity, making it necessary to deliver the radionuclide to every cell within a tumor cell population. These characteristics impose rigid restrictions on the nature of the carrier molecules for these types of particle emitters but successful targeting of these types of radionuclides could result in high therapeutic ratios. Most beta-emitting radionuclides are produced in nuclear rectors via neutron capture reactions; however, a few are produced in charged-particle accelerators. For radionuclides produced by direct neutron activation, the quantities and specific activities that can be produced are determined in large part by the cross-section of the target isotope and the flux of the reactor. Many applications (e.g., therapeutic bone agents, radiolabeled microspheres, radiocolloids) do not require high-specific activities and can therefore utilize the wide range of radionuclides that can be produced in sufficient quantity by direct neutron activation. Other applications (e.g., MAb labeling) require high-specific activity radionuclides in order to deliver a sufficient number of radionuclide atoms to the target site without saturating the target or compromising the integrity of the carrier molecule. Most radionuclides, produced at NCA levels in reactors, are produced via indirect reactions. High-specific activity beta emitters can also be obtained from radionuclide generator systems where the longer-lived parent radionuclide may be obtained from direct neutron activation, as a fission product, or from charged-particle accelerators. It is essential that the half-life of a radionuclide used in RNT be compatible with the rates of localization in target tissues and clearance of the carrier molecule from normal tissues. This consideration is especially important for the various MAbs and their fragments that are currently under investigation as carrier molecules to RIT.(ABSTRACT TRUNCATED AT 400 WORDS)
Half-Life↗
Bioassay alpha spectrometry: energy resolution as a function of sample source preparation and counting geometry.
Alpha particle counting is based on the response of an electronic counting system to an incident alpha particle. Alpha spectrometry is used in our employee surveillance bioassay program to measure the concentration of isotopes of Am, Pu and U contained on sample source preparations. Nuclides of Am, Pu and U are separated from the sample matrix by anion exchange and are electroplated on a stainless steel disc (Gautier and Gladney 1986). The plated source diameter is 12.7 mm. A tracer is added to the sample before anion exchange as a quality control procedure to provide a measure of chemical yield. Tracer alpha-particle emissions are recorded in a preassigned calibrated area of the energy spectrum and chemical recovery is calculated by the ratio of tracer counts per second divided by the tracer activity in becquerels (Bq). Percent tracer recovery may also be calculated by introducing the average counting efficiency factor in the denominator. Tracer yield is then used to provide a reliable estimate of the sample's analyte counts that are recorded in other preassigned energy dependent areas of the spectrum. The tracer spectrum in the presence or absence of other nuclides also provides evidence of the performance characteristics of the alpha spectrometer, for example, chamber vacuum and electronics. Electroplated samples are counted in any one of 96 detectors. The backgrounds of these detectors are maintained at less than 3 counts per 70,000 s over a 190 keV energy window to provide a limit of detection of less than 0.37 mBq per sample at the 95% confidence level. In this paper, resolution of the photopeak is shown to be a function of the source to detector distance and a function of degraded alpha energies due to Fe or other extraneous materials on the plated surface. Since our program is concerned only with low activity samples (less than 0.2 Bq) we encounter no significant problem with tailing when the resolution is less than 50 keV FWHM.
Alpha Particles↗
Cranial nerve damage in patients after alpha (heavy)-particle radiation to the pituitary.
The records of 161 patients were reviewed to determine if radiation damage had occurred following cranial irradiation. All of these patients had received alpha-particle radiation to their pituitary glands during the period when this form of therapy was given for diabetic retinopathy. Extraocular muscle palsy developed in 11 of these patients, iridoplegia in six, and fifth nerve damage in six. All of the palsies developed within a short period following their irradiation, and a definite dose relationship was present. The dose rate was approximately 100 rads/min for all cases. Fractionation varied but it is known for all cases. The estimated doses to the third, fourth, fifth, and sixth cranial nerves was calculated at a saggital plane 13 to 15 mm from the pituitary by using computer-drawn dosimetry charts for the respective aperture size. The energetic alpha particles were produced by the 184-in synchrocyclotron at Berkeley, Calif. A dose relationship for radiation palsies was apparent.
Adult↗
Thorium and actinium polyphosphonate compounds as bone-seeking alpha particle-emitting agents.
The present study explores the use of alpha-particle-emitting, bone-seeking agents as candidates for targeted radiotherapy. Actinium and thorium 1,4,7,10 tetraazacyclododecane N,N',N'',N''' 1,4,7,10-tetra(methylene) phosphonic acid (DOTMP) and thorium-diethylene triamine N,N',N'' penta(methylene) phosphonic acid (DTMP) were prepared and their biodistribution evaluated in conventional Balb/C mice at four hours after injection. All three bone-seeking agents showed a high uptake in bone and a low uptake in soft tissues. Among the soft tissue organs, only kidney had a relatively high uptake. The femur/kidney ratios for 227Th-DTMP, 228-Ac-DOTMP and 227Th-DOTMP were 14.2, 7.6 and 6.0, respectively. A higher liver uptake of 228Ac-DOTMP was seen than for 227Th-DTMP and 227Th-DOTMP. This suggests that some demetallation of the 228Ac-DOTMP complex had occurred. The results indicate that 225Ac-DOTMP, 227Th-DOTMP and 227Th-DTMP have promising properties as potential therapeutic bone-seeking agents.
Actinium↗
[Selective effect of inductors of apoptosis on the endoribonuclease activity of 26S proteasomes and alpha-RNP particles in K562 cells: possible involvement of 26S proteasomes and alpha-RNP in the regulation of RNA stability].
It has been shown that endoribonuclease activity of alpha-RNP particles and 26S proteasomes are changed under the action of inductors of programmed cell death. Treatment of K562 cells with inductors of apoptosis--doxorubicin (adriamycin) and diethylmaleate--lead to a significant stimulation of RNAse activity of alpha-RNP and to reduction of proteasome RNase activity. The enzymatic activity under study has been shown to be specifically and selectively dependent on phosphorylation of subunits of alpha-RNP particles and 26S proteasomes. The characteristics of RNAse activity of different subpopulations of proteasomes differ. The specificity of a subpopulation of proteasomes exported from the cell has been demonstrated. Proteasome and alpha-RNP involvement in the coordinated control of stability of various specific messenger RNA molecules is suggested, and one of the mechanisms of this control might be the export of specific subpopulation of proteasomes from the cell.
Apoptosis↗
Effects of MA 956 superalloy and alpha-alumina particles on some markers of human osteoblastic cells in primary culture.
One of the problems associated with the modern biomaterials used in prostheses is osteolysis, which, although its exact origin is unknown, has been associated with wear particles. Osteoblasts seem to participate directly in this phenomenon. This paper investigates in vitro cellular response to the wear particles from the metal substrate and ceramic covering (alpha-alumina) of a new titanium yttrium aluminum alloy, MA 956, that has been proposed as a biomaterial because of its exceptional mechanical and electrochemical properties. The effect of different sizes (10 and 80 microm) of MA 956 and alpha-alumina particles on osteoblast function was studied in primary human bone cell cultures. Cells were harvested from trabecular bone fragments obtained during knee arthroplasty. Osteoblastic cell response to the particles was measured by assaying C-terminal type I procollagen (PICP), alkaline phosphatase, and osteocalcin secretion, with and without 1.25(OH)(2)D(3) stimulation, in the cell-conditioned medium. Both sizes of MA 956 and alpha-alumina particles decreased PICP secretion in nonstimulated osteoblastic cells, but this secretion was not affected in the cultures stimulated with 1.25(OH)(2)D(3). Only the 10 microm alpha-alumina particles inhibited alkaline phosphatase activity in 1.25(OH)(2)D(3)-stimulated and nonstimulated cultures. The rise in osteocalcin levels after 1.25(OH)(2)D(3) stimulation was lower in the presence of the 10 microm MA 956 particles than in the presence of alpha-alumina particles. Although both materials seem to have directly affected in vitro osteoblastic cell function, the increase in osteocalcin levels after 1.25(OH)(2)D(3) stimulation was lower after exposure to MA 956 particles than the increase observed after exposure to alpha-alumina particles. Therefore, it does not seem that osteocalcin stimulated bone resorption, suggesting that MA 956 would be less likely to provoke osteolysis.
Aged↗
The two-stage clonal expansion model as an example of a biologically based model of radiation-induced cancer.
A model with two stages and clonal expansion (TSCE) is reviewed as a prototype for biologically based models of cancer development. Applications of the TSCE model to data sets for animals and humans for particle radiation (alpha particles) are presented. The results suggest that the radiation not only influences the initiating mutation, but may also act as a promoter. A possible mechanism for the promoting action is described. The consequences of these results for the shapes of the radiation dose-response curves at low doses and dose rates are discussed.
Alpha Particles↗
Partial deletion of p53 gene in alpha particle-induced transformant of Syrian hamster embryo cells.
The mutation of p53 gene was detected in Syrian hamster embryo (SHE) cells neoplastically initiated with alpha particles. The level of the p53 mRNA in transformant was obviously higher than that in non-irradiated counterpart, as measured by Northern blot analysis of total RNA. A pair of primers were designed based on p53 cDNA sequence to produce the whole length of coding sequence about 1.2 kilobase (Kb) by reverse transcription of mRNA followed by the polymerase chain reaction (RT-PCR), but the length of fragment amplified from transformant mRNA was about 0.3 Kb, remarkably shorter than that from normal SHE cells. Immunohistochemical analysis of p53 protein showed that no heavy staining was found on slice of tumor derived from transformant inoculated in nude mice with hamster specific p53 monocloned antibody HD200. The results implied that p53 gene had been mutated by deletion, which might lead to loss of p53 protein expression but the increased expression of p53 remained in alpha particle-induced SHE transformant.
Animals↗
Photonuclear dose calculations for high-energy photon beams from Siemens and Varian linacs.
The dose from photon-induced nuclear particles (neutrons, protons, and alpha particles) generated by high-energy photon beams from medical linacs is investigated. Monte Carlo calculations using the MCNPX code are performed for three different photon beams from two different machines: Siemens 18 MV, Varian 15 MV, and Varian 18 MV. The linac head components are simulated in detail. The dose distributions from photons, neutrons, protons, and alpha particles are calculated in a tissue-equivalent phantom. Neutrons are generated in both the linac head and the phantom. This study includes (a) field size effects, (b) off-axis dose profiles, (c) neutron contribution from the linac head, (d) dose contribution from capture gamma rays, (e) phantom heterogeneity effects, and (f) effects of primary electron energy shift. Results are presented in terms of absolute dose distributions and also in terms of DER (dose equivalent ratio). The DER is the maximum dose from the particle (neutron, proton, or alpha) divided by the maximum photon dose, multiplied by the particle quality factor and the modulation scaling factor. The total DER including neutrons, protons, and alphas is about 0.66 cSv/Gy for the Siemens 18 MV beam (10 cm x 10 cm). The neutron DER decreases with decreasing field size while the proton (or alpha) DER does not vary significantly except for the 1 cm x 1 cm field. Both Varian beams (15 and 18 MV) produce more neutrons, protons, and alphas particles than the Siemens 18 MV beam. This is mainly due to their higher primary electron energies: 15 and 18.3 MeV, respectively, vs 14 MeV for the Siemens 18 MV beam. For all beams, neutrons contribute more than 75% of the total DER, except for the 1 cm x 1 cm field (approximately 50%). The total DER is 1.52 and 2.86 cSv/Gy for the 15 and 18 MV Varian beams (10 cm x 10 cm), respectively. Media with relatively high-Z elements like bone may increase the dose from heavy charged particles by a factor 4. The total DER is sensitive to primary electron energy shift. A Siemens 18 MV beam with 15 MeV (instead of 14 MeV) primary electrons would increase by 40% the neutron DER and by 210% the proton + alpha DER. Comparisons with measurements (neutron yields from different materials and neutron dose equivalent) are also presented. Using the NCRP risk assessment method, we found that the dose equivalent from leakage neutrons (at 50-cm off-axis distance) represent 1.1, 1.1, and 2.0% likelihood of fatal secondary cancer for a 70 Gy treatment delivered by the Siemens 18 MV, Varian 15 MV, and Varian 18 MV beams, respectively.
Electrons↗
A technique for high-sensitivity alpha autoradiography of bronchial epithelium tissue.
A technique for low-level alpha-particle autoradiography of bronchial epithelium utilising the plastic track detector, CR-39, is described. This plastic is new to the field of nuclear track detection and is very sensitive to alpha-particles. The recording properties of CR-39 for alpha-particles are described in detail and the technique for autoradiography discussed. This technique includes two methods of background reduction enabling activities as low as 2 alpha-particles cm-2 to be detected. The location of the point of emission of an alpha-particle from the tissue surface can be determined to an accuracy of a few micrometers. Determination of the lower limit to the energy of individual alpha-particles is possible from measurements of their range in the plastic. Examples are given of the determination of the microdistribution of alpha-particle active nuclei in bronchial tissue including the observation of two 'hot-spots' in the epithelium sample which are attributed to the presence of small particles of uranium with its daughter products.
Aged↗
Effects of polyethylene and alpha-alumina particles on IL-6 expression and secretion in primary cultures of human osteoblastic cells.
The effect of two biomaterials, polyethylene and alpha-alumina, on interleukin-6 (IL-6) secretion and expression has been studied in human osteoblasts in primary culture. Human osteoblastic cells were derived from fresh trabecular bone explants removed during total knee arthroplasty. On reaching confluence, cells were subcultured in 6 well plates; the resulting subcultures were incubated until confluence and polyethylene or alpha-alumina particles were added to some while the rest were left as controls. The IL-6 mRNA levels were assessed by reverse transcription (RT) followed by polymerase chain reaction (PCR). IL-6 secretion was measured in the conditioned medium. The IL-6 expression was higher in the presence of both biomaterials. Maximum expression occurred in response to a dose of 50 mg particles well with both biomaterials and was greater after polyethylene particle addition than after alpha-alumina particle addition at this dose. The maximum IL-6 secretion elicited by alpha-alumina was produced at 10 mg particles well while maximum response with polyethylene required 50 mg well. At a dose of 10 mg/well, alpha-alumina particles induced more secretion than 10 mg of polyethylene particles. Nevertheless, at a dose of 50 mg/well maximum secretion was produced with polyethylene particles. In conclusion and in our experimental conditions, polyethylene as well as alpha-alumina increased both the expression and the secretion of IL-6 in human osteoblastic cells in primary culture and stimulation from polyethylene appears stronger than that from alpha-alumina at the same dose.
Aluminum Oxide↗
The bystander effect in radiation oncogenesis: I. Transformation in C3H 10T1/2 cells in vitro can be initiated in the unirradiated neighbors of irradiated cells.
It has long been accepted that radiation-induced genetic effects require that DNA be hit and damaged directly by the radiation. Recently, evidence has accumulated that in cell populations exposed to low doses of alpha particles, biological effects occur in a larger proportion of cells than are estimated to have been traversed by alpha particles. The end points observed include chromosome aberrations, mutations and gene expression. The development of a fast single-cell microbeam now makes it possible to expose a precisely known proportion of cells in a population to exactly defined numbers of alpha particles, and to assay for oncogenic transformation. The single-cell microbeam delivered no, one, two, four or eight alpha particles through the nuclei of all or just 10% of C3H 10T1/2 cells. We show that (a) more cells can be inactivated than were actually traversed by alpha particles and (b) when 10% of the cells on a dish are exposed to alpha particles, the resulting frequency of induced transformation is not less than that observed when every cell on the dish is exposed to the same number of alpha particles. These observations constitute evidence suggesting a bystander effect, i.e., that unirradiated cells are responding to damage induced in irradiated cells. This bystander effect in a biological system of relevance to carcinogenesis could have significant implications for risk estimation for low-dose radiation.
Animals↗
No increase in radiation-induced chromosome aberration complexity detected by m-FISH after culture in the presence of 5'-bromodeoxyuridine.
The thymidine analogue, 5'-bromodeoxyuridine (BrdU), is a known mutagen that is routinely introduced into culture media for subsequent Harlequin stain analysis and determination of cell cycle status. Previously, we examined the induction of chromosome aberrations in human peripheral blood lymphocytes (PBL) known to be in their 1st cell division following exposure to a low dose (0.5 Gy, average one alpha-particle per cell) of high-LET alpha-particles. We found complex chromosome aberrations to be characteristic of exposure to high-LET radiation and suggested the features of complex exchange to reflect qualitatively the spatial deposition of this densely ionising radiation. To exclude the possibility that BrdU addition post-irradiation influenced the complexity of chromosomal damage observed by m-FISH, the effect of increasing BrdU concentration on aberration complexity was investigated. Comparisons between BrdU concentration (0, 10 and 40 microM) and between sham- and alpha-particle-irradiated PBL, were made both independently and in combination to enable discrimination between BrdU and high-LET radiation effects. Aberration type, size, complexity and completeness were assessed by m-FISH, and the relative progression through cell division was evaluated. We found no evidence of any qualitative difference in the complexity of damage as visualised by m-FISH but did observe an increase in the frequency of complex exchanges with increasing BrdU concentration indicative of altered cell cycle kinetics. The parameters measured here are consistent with findings from previous in vitro and in vivo work, indicating that each complex aberration visualised by m-FISH is characteristic of the structure of the high-LET alpha-particle track and the geometry of cell irradiated.
Adult↗
Homogeneous Precipitation of Uniform alpha-Fe2O3 Particles from Iron Salts Solutions in the Presence of Urea.
Uniform alpha-Fe2O3 particles within the nanometer range (100-300 nm) have been obtained by precipitation of iron (III) perchlorate in the presence of urea. Different morphology, from spheres to ellipsoidal particles with axial ratio up to approximately 10, was obtained by adding to the initial solution increasing amounts of phosphate anions up to 7 x 10(-3) M. The main targets of this work are the reduction in particle size and precipitation time and the increase of the particles axial ratio, keeping a narrow particle size distribution, in comparison to other methods previously developed to obtain homogenous alpha-Fe2O3 particles. A detailed analysis of the reaction products and a systematic study of the influence of the different precipitation conditions on the characteristics of the resulting particles have been carried out. Finally, some information on the formation mechanism of the ellipsoidal hematite particles in the iron (III) salt-urea-phosphate system is also given. Copyright 1999 Academic Press.
Journal Article↗
Ionizing radiation-induced mutation of human cells with different DNA repair capacities.
We have observed significant differences in the response to ionizing radiation of two closely related human cells lines, and now compare the effects on these lines of both low and intermediate LET radiation. Compared to TK6, WTK1 has an enhanced X-ray survival, and is also more resistant to cell killing by alpha-particles. The hprt locus is more mutable in WTK1 than in TK6 by both X-rays and alpha-particles. WTK1 is also more mutable by alpha-particles than by X-rays at the hprt locus. X-ray-induced mutation at the heterozygous tk locus in WTK1 is about 25 fold higher than in TK6, while alpha-particle-induced mutation is nearly 50 fold higher at this locus. Also, the slowly growing tk- mutants, which comprise the majority of spontaneous and X-ray-induced tk- mutants of TK6, were not induced significantly by alpha-particles. Previously, we showed that TK6 has a reduced capacity for recombination compared with WTK1, and therefore, these results indicate that recombinational repair may contribute to both cell survival and mutation-induction following exposure to ionizing radiation. Such a mechanism may aid cell survival, but could also result in increased deleterious effects such as the unmasking of recessive mutations in cancer suppresser genes.
Alpha Particles↗
Revised organ partition of thorium-232 in thorotrast patients.
Risk estimates for internally deposited alpha particles in humans, such as those for alpha-particle-induced leukemia, have been derived from data on the toxicity of (232)Th in patients injected with Thorotrast. Their derivation requires both epidemiological data and organ doses calculated from the volume of Thorotrast injected and a knowledge of its pattern of deposition within the body. However, accumulating evidence suggests that the organ partition of (232)Th that has commonly been used for dosimetry (i.e. liver:spleen:red bone marrow: others tissues = 59:29:9:3) is inaccurate. In the present study, the organ distribution of (232)Th has been recalculated using a revised averaging method and both published data and our own unpublished data. For the three major organs of deposition (liver, spleen and bone marrow), activity concentration data were selected from 27 published papers and data sets including 140 newly compiled Japanese cases. For organs of minor storage, both published data for 38 German and 24 Japanese autopsy cases and new data were used. The revised estimate of the relative partition of (232)Th among the above organs was 53:14:25:8. It follows that doses calculated to date are essentially correct for the liver but are too high for the spleen and about three times too low for the red bone marrow. This suggests that the risk of alpha-particle-induced leukemia, per unit of alpha-particle dose, in Thorotrast patients is about three times lower than previously thought.
Bone Marrow↗