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PubMedDate not supplied

[Concept of the effect of low doses of ionizing radiation on cells and its possible use in the interpretation of medical-biological consequences].

A concept is proposed where the events induced by low doses of ionizing radiation with low linear energy transfer have different script than those induced by high doses. Its essence consist in the existence of a small fraction (subpopulation) in clonal heterogeneous population whose cells are determined for a specific programmed response induced by a number of action that are potentially able (at high doses) to decrease the survival of the given population. The function of the postulated cell is a deliberate sacrifice necessary for formation of evolutionary reserve. A mechanism of this response is based on an autogeneration of wide-scale genome rearrangements in cells and is not connected with direct influence of genetically hazardous agents on DNA. This leads to arising of a number of genetic variants (evolutionary reserve cells). Selection among them enhancing survival of the population may in the same time lead to harmful consequences for the organism (if there are malfunctions of the immune system). Medical-biological consequences of the effect of low doses are associated with the appearance of such clones and biologically active products secreted from the exposed cells. Mechanisms responsible for the above phenomena are discussed.

Cell Nucleus↗

PubMed1992

Emesis in ferrets following exposure to different types of radiation: a dose-response study.

Ferrets were exposed to gamma rays (60Co), fission neutrons, high-energy electrons (18.5 MeV) or iron particles (56Fe, 600 MeV/amu) in order to establish the dose-response relationships for emesis following exposure to different types of radiation. The results showed that the mean effective doses (ED50s) for iron particles (35 cGy) and neutrons (40 cGy) were similar. High-energy electrons were the least effective radiation, with an ED50 of 138 cGy. Gamma rays, with an ED50 of 95 cGy, showed an intermediate effectiveness. The results suggest that the relative effectiveness of different types of radiation generally increases with an increase in linear energy transfer (LET), although LET is not completely predictive of relative behavioral effectiveness.

Animals↗

PubMed2004

Tissue distribution of Thorotrast and role of internal irradiation in carcinogenesis.

Carcinogenesis in Thorotrastosis has been assumed due to direct bombardment by alpha-particle with high linear energy transfer during decay of 232Th. To revisit the mechanism of carcinogenesis by Thorotrast (THR), we examined the tissue distribution of THR granules and two-dimensional distribution of radioactivity in the organs of Thorotrastosis patients and studied their spatial relationship to histopathological changes. The high radioactivity in the patients' organ was predominantly derived from decay of Thorium series and showed unique distribution, while the far lower natural radioactivity was mainly from Uranium series decay and fairly evenly distributed. It was found that a large majority of THR granules were phagocytized by macrophages and were embedded in extensive fibrosis. Cancer was rarely in the center of THR deposition but rather at a distance from the deposits. These observations may indicate that the predominant feature of THR deposition is the tissue damage by direct hit of alpha-particles and subsequent fibrosis. The effect of THR resembles action of toxic chemical agents, as several authors have pointed out. We therefore assume that carcinogenesis in Thorotrastosis is a combination of events, such as regeneration of liver tissue after radiation damage, emission of secondary electrons, ionization of the surrounding tissue, and beta- or gamma-ray from daughter nuclei of Thorium (Th). In this context, the role of alpha-particle is important but more intriguing.

Aged↗

PubMedDate not supplied

[Neoplastic transformation of mouse fibroblasts under the influence of high-energy protons and gamma-rays].

Oncoginic transformations of mouse fibroblasts C3H10T1/2 after exposure to proton energies 150 and 584 MeV were compared with fibroblast effects of gamma-radiation. Prior to exposure, cell populations (2.7 x 10(3) cells/cm2) were inoculated in plastic vials with the surface area of 75 cm2 and cultivated 11 days. Survivability was determined by comparing the number of cell colonies in irradiated and non-irradiated (control) vials. Transformation rate was calculated by dividing the total transformation focus number by the number of survived cells in a vial. Rate of oncogenic transformations after gamma- and proton (584 MeV) irradiation was essentially identical, i.e. the parameter grew rapidly at the doses < 1 Gy and slowed down at the doses > 1 Gy. In the dose interval between 1 and 5 Gy, transformation rate for proton energy 150 MeV was found low compared with gamma-radiation and proton energy 584 MeV. It is hypothesized that the different transformation rate after exposure to proton energy 150 MeV is linked with the high linear energy transfer as compared with the proton energy of 584 MeV and gamma-radiation.

Animals↗

PubMed2005

The promise of targeted {alpha}-particle therapy.

The use of monoclonal antibodies to deliver radioisotopes directly to tumor cells has become a promising strategy to enhance the antitumor effects of native antibodies. Since the alpha- and beta-particles emitted during the decay of radioisotopes differ in significant ways, proper selection of isotope and antibody combinations is crucial to making radioimmunotherapy a standard therapeutic modality. Because of the short pathlength (50-80 microm) and high linear energy transfer ( approximately 100 keV/microm) of alpha-emitting radioisotopes, targeted alpha-particle therapy offers the potential for more specific tumor cell killing with less damage to surrounding normal tissues than beta-emitters. These properties make targeted alpha-particle therapy ideal for the elimination of minimal residual or micrometastatic disease. Radioimmunotherapy using alpha-emitters such as (213)Bi, (211)At, and (225)Ac has shown activity in several in vitro and in vivo experimental models. Clinical trials have demonstrated the safety, feasibility, and activity of targeted alpha-particle therapy in the treatment of small-volume and cytoreduced disease. Further advances will require investigation of more potent isotopes, new sources and methods of isotope production, improved chelation techniques, better methods for pharmacokinetic and dosimetric modeling, and new methods of isotope delivery such as pretargeting. Treatment of patients with less-advanced disease and, ultimately, randomized trials comparing targeted alpha-particle therapy with standard approaches will be required to determine the clinical utility of this approach.

Alpha Particles↗

PubMedDate not supplied

[The relative biological effectiveness of alpha-radiation during human lung exposure to irradiation].

The assessment of the relative biological effectiveness (RBE) for alpha-radiation was held in the cases of inhalation of radon progeny and incorporation of plutonium in lungs. It is based on simulation of lung cancer radiation risk for different types of radiation. Specific radiation risk models developed according to the results of direct epidemiological studies are used for the simulation. These include two published risk models for uranium miners and nuclear workers of the Mayak facilities in the former Soviet Union. Additionally two lung cancer risk models are developed and described for the following cases: population indoor radon exposure and low-linear-energy-transfer reference radiation exposure. By the results of lifetime lung cancer risk simulation the RBE values range from 11 to 12 and from 1.7 to 4.9 for the cases of plutonium incorporation and of radon progeny exposure accordingly. The significant uncertainty of radiation risk models results in significant variation of RBE assessments. Rough estimations of RBE values 90% confidence interval are from unit fraction to 25 and from 2 to 50 for the cases of radon progeny exposure and plutonium incorporation accordingly.

Alpha Particles↗

PubMed1992

Microbeam studies of the sensitivity of structures within living cells.

Determining the biological effects of low doses of radiation with high linear energy transfer (LET) is complicated by the stochastic nature of charged-particle interactions. Populations of cells exposed to very low radiation doses contain a few cells which have been hit by a charged particle, while the majority of the cells receive no radiation damage. At somewhat higher doses, a few cells receive two or more events. Because the effects of damage produced by separate events can interact in the cell, we have had to make assumptions about the nature of these interactions in order to interpret the results of the experiments. Many of those assumptions can be tested if we can be sure of the number of charged-particle events which occur in individual cells, and correlate this number with the biological effect. We have developed a special irradiation facility at Pacific Northwest Laboratory (PNL) to control the actual number of charged particle tracks that pass through cell nuclei. The beam from a 2 MeV tandem accelerator is collimated to approximately 5 microns. Cells, grown in special dishes with 1.5 microns thick plastic bottoms, are positioned so that the desired portion of the cell aligns with the collimator. A shutter in the beam line is opened and closed after the desired number of particle tracks has been counted. This approach can be used to investigate the effects of the interaction between irradiated and unirradiated cells in an organized system, as well as to study the effects of spatial and temporal distribution of radiation damage within single cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2005

Trifunctional somatostatin-based derivatives designed for targeted radiotherapy using auger electron emitters.

UNLABELLED: Auger electron-emitting radionuclides have potential for the therapy of small-size cancers because of their high level of cytotoxicity, low-energy, high linear energy transfer, and short-range biologic effectiveness. Biologic effects are critically dependent on the subcellular (and even subnuclear) localization of these radionuclides. Our goals were the design, synthesis, and in vitro preclinical assessment of new trifunctional conjugates of somatostatin that should aim at the nucleus and, therefore, ensure a longer retention time in the cell, a close approximation to the DNA, and the success of Auger electron emitters in targeted radionuclide therapy as well as also improve other targeted therapy strategies. METHODS: Three trifunctional derivatives of [(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)0,Tyr3]octreotide (DOTA-TOC) bearing the nuclear localization signal (NLS) (of simian virus 40 large-T antigen) PKKKRKV in 3 different positions relative to the somatostatin analog sequence were synthesized using solid and solution phase peptide synthesis. These compounds together with DOTA-TOC and DOTA-NLS derivatives were labeled with 111In and tested for binding affinity, internalization, externalization, and nuclei localization on AR4-2J cells and on human embryonic cells stably transfected with sst2A. RESULTS: The two N-terminal derivatives preserved the sstr2A binding affinity. Their rate of internalization in all tested sstr-expressing cell lines was always superior for the trifunctional derivatives in comparison with the parent compound. A 6-fold increase in cellular retention from the total internalized activity and a 45-fold higher accumulation in the cell nuclei were found for one of the N-terminally modified compounds compared with [111In]-DOTA-TOC. The C-terminal conjugate was inferior in all tests compared with the parent compound. CONCLUSION: These encouraging results support our hypothesis that an additional NLS sequence to the DOTA-TOC could not only provide a better carrier for Auger electron-emitting radionuclides but also ensure a longer radioactivity retention time in the tumor cell.

Cell Line↗

PubMed1992

Radiation sensitivity in vitro of primary tumors and metastatic lesions of malignant melanoma.

The radiation sensitivity of cells isolated directly from surgical specimens of the primary tumor and one to three distant metastases in ten different melanoma patients was measured in vitro using the Courtenay soft agar colony assay. Dose-response curves were fitted to the cell survival data by the method of least squares using the multitarget-single hit and the linear-quadratic models. The ten patients could be divided into three distinct groups. Group I consisted of four patients with radioresistant primary tumors (D0s from 1.38 +/- 0.06 Gy to 1.69 +/- 0.08 Gy). The radiation sensitivity of the metastases (D0s from 1.33 +/- 0.10 Gy to 1.73 +/- 0.06 Gy) was not significantly different from that of the primary tumor in this group; i.e., no heterogeneity was observed. Group II consisted of three patients with radiosensitive primary tumors (D0s from 0.84 +/- 0.06 Gy to 0.91 +/- 0.05 Gy). Heterogeneity was not observed in this group either; i.e., all metastases were radiosensitive (D0s from 0.85 +/- 0.05 Gy to 1.00 +/- 0.06 Gy). Group III consisted of three patients with a heterogeneous disease. The primary tumor of all patients in this group was radiosensitive (D0s from 0.85 +/- 0.05 Gy to 1.03 +/- 0.05 Gy). The most radioresistant metastasis in each patient was significantly (P much less than 0.05) more resistant (D0s from 1.46 +/- 0.06 Gy to 1.56 +/- 0.07 Gy) than the primary tumor. None of the metastases were significantly more radiosensitive than the primary tumor in any patient. These observations suggest that the progression of tumors to increased levels of malignancy includes the increased ability to become radioresistant, and it may be speculated that similar genomic alterations are responsible for the development of the metastatic and the radioresistant tumor cell phenotype. If so, this may have severe implications for the treatment of metastatic malignant melanoma with low linear energy transfer ionizing radiation as well as for the development of predictive assays for tumor treatment sensitivity.

Adult↗

PubMed1991

Biological effectiveness of high-energy protons: target fragmentation.

High-energy protons traversing tissue produce local sources of high-linear-energy-transfer (LET) ions through nuclear fragmentation. We examine the contribution of these target fragments to the biological effectiveness of high-energy protons using the cellular track model. The effects of secondary ions are treated in terms of the production collision density using energy-dependent parameters from a high-energy fragmentation model. Calculations for mammalian cell cultures show that at high dose, at which intertrack effects become important, protons deliver damage similar to that produced by gamma rays, and with fragmentation the relative biological effectiveness (RBE) of protons increases moderately from unity. At low dose, where sublethal damage is unimportant, the contribution from target fragments dominates, causing the proton effectiveness to be very different from that of gamma rays with a strongly fluence-dependent RBE. At high energies, the nuclear fragmentation cross sections become independent of energy. This leads to a plateau in the proton single-particle-action cross section, below 1 keV/micron, since the target fragments dominate.

Cell Survival↗

PubMed2006

[Clinical experience of carbon ion radiotherapy for malignant tumors].

The carbon ion (C-ion) beams provide unique advantageous biological and physical properties in radiotherapy (RT) for malignant tumors. C-ion beams have a high relative biological effectiveness (RBE) resulting from the high linear energy transfer (LET). In terms of their physical characteristics, C-ion beams exhibit a spread-out Bragg peak (SOBP) and make for a better dose distribution of the target volume by specified beam modulations. Between June 1994 and August 2005, a total of 2,371 patients with malignant tumors were registered in phase I/II dose-escalation studies and clinical phase II trials using C-ion beams generated at Heavy Ion Medical Accelerator in Chiba (HIMAC). In the initial dose-escalation studies, grade 3 or more late rectal complications had developed in some patients. However, the adverse effects were resolved because of the use of appropriate dose levels and modification of the radiation technique. C-ion beams can carry out hypofractionated radiotherapy with a large fraction dose and reduce the overall treatment times compared with conventional radiotherapy. They can also achieve better local tumor control even for radio-resistant tumors such as malignant melanoma, hepatocellular carcinoma and bone and soft tissue sarcomas with minimal morbidity to the normal surrounding tissues.

Bone Neoplasms↗

PubMed2006

Radiation-induced biologic bystander effect elicited in vitro by targeted radiopharmaceuticals labeled with alpha-, beta-, and auger electron-emitting radionuclides.

UNLABELLED: Recent studies have shown that indirect effects of ionizing radiation may contribute significantly to the effectiveness of radiotherapy by sterilizing malignant cells that are not directly hit by the radiation. However, there have been few investigations of the importance of indirect effects in targeted radionuclide treatment. Our purpose was to compare the induction of bystander effects by external beam gamma-radiation with those resultant from exposure to 3 radiohaloanalogs of metaiodobenzylguanidine (MIBG): (131)I-MIBG (low-linear-energy-transfer [LET] beta-emitter), (123)I-MIBG (potentially high-LET Auger electron emitter), and meta-(211)At-astatobenzylguanidine ((211)At-MABG) (high-LET alpha-emitter). METHODS: Two human tumor cell lines-UVW (glioma) and EJ138 (transitional cell carcinoma of bladder)-were transfected with the noradrenaline transporter (NAT) gene to enable active uptake of MIBG. Medium from cells that accumulated the radiopharmaceuticals or were treated with external beam radiation was transferred to cells that had not been exposed to radioactivity, and clonogenic survival was determined in donor and recipient cultures. RESULTS: Over the dose range 0-9 Gy of external beam radiation of donor cells, 2 Gy caused 30%-40% clonogenic cell kill in recipient cultures. This potency was maintained but not increased by higher dosage. In contrast, no corresponding saturation of bystander cell kill was observed after treatment with a range of activity concentrations of (131)I-MIBG, which resulted in up to 97% death of donor cells. Cellular uptake of (123)I-MIBG and (211)At-MABG induced increasing recipient cell kill up to levels that resulted in direct kill of 35%-70% of clonogens. Thereafter, the administration of higher activity concentrations of these high-LET emitters was inversely related to the kill of recipient cells. Over the range of activity concentrations examined, neither direct nor indirect kill was observed in cultures of cells not expressing the NAT and, thus, incapable of active uptake of MIBG. CONCLUSION: Potent toxins are generated specifically by cells that concentrate radiohalogenated MIBG. These may be LET dependent and distinct from those elicited by conventional radiotherapy.

Bystander Effect↗

PubMed1996

Differentiation and delayed cell death in embryonal stem cells exposed to low doses of ionising radiation.

Embryonal stem cells have been used to study the effects of environmentally relevant doses of radiation on cell death and differentation. The ES cells were found to have a greater than 60% chance of surviving the traversal of a single alpha-particle, the lowest possible dose of high linear energy transfer radiation a cell may receive. The ES cells appeared to possess the cell cycle checkpoints believed to prevent the transmission of the radiation damage. However, delayed effects were observed in the progeny. An increased incidence of apoptosis and haempoietic differentiation capacity was found to persist in the ES cell population over many cell divisions. Since both cell death and differentiation are known to play a key role in tissue kinetics, an ES cell model will provide a valuable and versatile cell system for studying the role of cell death and differentiation in the pathology of radiogenic diseases.

Journal Article↗

PubMed1991

Relative biological effectiveness for neutron carcinogenesis in monkeys and rats.

The risks of total-body irradiation with large doses of X rays (average dose 6.7 Gy) and fission neutrons (average dose 3.4 Gy) were investigated by keeping a group of long-term surviving monkeys from an experiment on acute effects under continuous observation. On the basis of the number of animals developing tumors in each group as a function of the total observation period and the average absorbed dose, relative biological effectiveness (RBE) values between 4 and 5 have been derived at these high dose levels. In experiments on mammary carcinogenesis in rats the highest RBE values are observed for neutrons with energies of 0.43 to 1 MeV as produced by the p + T reaction or by the fission process. Based upon linear dose-response curves for neutrons and X rays, a maximum RBE value of 15 was observed for induction of adenocarcinomas in WAG/Rij rats. Appreciably higher RBE values would be obtained if the results of the gamma-ray exposure, indicating a nearly quadratic dose-response relationship, were used as a baseline. For radiation protection applications it should be realized, however, that such an increase will be caused by the lower efficiency of low-linear-energy-transfer radiation rather than by an increase in efficiency of the neutron irradiation at low doses.

Adenocarcinoma↗

PubMed1991

Perspectives on fast-neutron mutagenesis of human lymphoblastoid cells.

The effects of low-fluence exposures to (Pu, Be) neutrons (En = 4.2 MeV) have been studied in a sensitive human B-lymphoblastoid cell line, TK6. Mutations were scored for two genetic loci, hypoxanthine phosphoribosyltransferase (hgprt) and thymidine kinase (tk), as a function of dose and dose rate. For exposures limited to less than one cell cycle, the mutation frequency for the hgprt locus was 1.92 X 10(-7)/cGy. When exposures were protracted over multiple cell generations, mutation yields were increased to 6.07 X 10(-7)/cGy. Similar yields were obtained for the induction of tk-deficient mutants with a normal cell generation time (tk-ng) when exposures were carried out at very low dose rates over multiple cell generations. In the series of data presented here, the results obtained for short-duration neutron exposures are compared with data obtained for monoenergetic heavy charged particles of defined linear energy transfer (LET) produced at the BEVALAC accelerator at Lawrence Berkeley Laboratory. TK6 cells have been exposed to beams ranging in atomic number from 20Ne to 40Ar over an energy range from 330 to 670 MeV/amu. Mutation induction was evaluated for both loci for a subset of these beams. The results obtained with 20Ne ions of 425 MeV/amu (LET = 32 keV/microns) and 28Si ions of 670 MeV/amu (LET = 50 keV/microns) closely resemble the mutation yields obtained for brief exposures to (Pu, Be) neutrons. The nature of alterations in DNA structure induced within the tk locus of tk-ng mutants is reviewed for a series of neutron-induced mutants and a series of mutants induced by exposure to 40Ar ions (470 MeV/amu, LET = 95 keV/microns). The mutational spectra for these two types of mutants were similar and were dominated by allele loss mutations. Multilocus deletions inclusive of the c-erbA1 locus were common among tk-deficient mutants induced by these densely ionizing radiations. For the mutants induced by 40Ar ions, it is likely that the mutations were produced by the traversal of the chromosome by a single particle.

Argon↗

PubMed1991

Basic radiobiological investigations of fast neutrons.

The radiobiological properties of a cyclotron-produced 43-MeV (p----Be) fast-neutron beam relative to gamma rays have been investigated using Chinese hamster V79 cells in culture. As expected, the relative biological effectiveness (RBE) of this neutron beam for cell killing was shown to increase as dose decreased, and the effectiveness per unit dose was slightly less compared to a 25-MeV (d----Be) neutron beam. By tracing single cells that formed microcolonies after irradiation, we found cell proliferation kinetics to be retarded to a greater extent by fast neutrons than by gamma irradiation. Following either neutron or gamma irradiation, a fraction of the irradiated cells failed to divide in the first postirradiation division and another fraction could produce as many as four generations of progeny before proliferation stopped. The properties of these cells presumed to be destined for death suggest that more than one mechanism and/or multistep process underlies the radiation-induced proliferative death. The fast-neutron beam was also found to be more effective quantitatively than gamma rays in producing DNA double-strand breaks (DSBs, measured by nondenaturing filter elution), and G1-phase chromosome fragments (measured by the premature chromosome condensation technique). However, the reverse was observed for DNA single-strand breaks (SSBs, measured by alkaline filter elution or hydroxylapatite uncoiling). Interestingly, both fast neutrons and gamma rays produced a large component of SSBs and DSBs with a fast-rejoining time constant of about 2-5 min, which appears to be independent of dose. The latter results could not resolve the possibility of lengthening the repair-time constant by increasing radiation dose within the range that is reflected by the shoulder of the survival curve, and consequently did not support the idea of repair saturation as a mechanism for the presence of the shoulder. The RBE for the hypoxanthine phosphoribosyl transferase mutation frequency per survivor at the 10% survival level was estimated to be 2.5, a value that is comparable to the RBE (2.1) for cell killing at the same survival level. Although most of the above-mentioned findings are compatible qualitatively with the relatively high-LET (linear energy transfer) nature associated with the fast-neutron beam, the significance of the action attributable to the mixture of LET could not be delineated in these experiments. Further, the biological significance of DSBs and chromosome aberration and the molecular mechanisms responsible for the repair and expression of these damaging processes remain to be elucidated.

Animals↗

PubMed1991

Alpha-particle irradiation-induced change in bronchopulmonary macrophage morphology, in vitro.

Bronchopulmonary macrophages, isolated from canine lungs by saline lavage and grown in tissue culture for short periods, were acutely irradiated with a range of doses of either Americium-241 alpha particles (0.03-48 Gy) or 250 keV x-rays (0.5-24 Gy). Following a 24-hour reincubation and "expression" period, cells were examined for radiation-induced changes in overall viability, as well as in cell morphology and ultrastructure. Results indicated that neither quality of radiation had much effect on cell viability over dose ranges examined, but substantial changes in cell volume, surface topography, and cytoplasmic features were noted, especially in the alpha-particle-irradiated specimens. Results support the concept that the limiting plasma membrane of the targeted macrophage is a sensitive subcellular target for ionizing radiation, especially high-linear-energy-transfer heavy particles.

Alpha Particles↗

PubMed1991

The response of ataxia-telangiectasia lymphoblastoid cells to neutron irradiation.

The response of control and ataxia-telangiectasia (A-T) cells to increasing doses of high-linear-energy-transfer (LET) ionizing radiation (neutrons) was compared. Ataxia-telangiectasia cells were markedly more sensitive to neutron irradiation than were control cells. The D0 value for the two A-T cell lines was 0.4 Gy while the value for controls was approximately 1.4 Gy. Fast neutrons were considerably more effective than gamma rays in inducing cell death in both cell types, but the sensitivity factor remained approximately the same as with gamma rays. A minimal depression of DNA synthesis was observed in ataxia-telangiectasia cells after neutron irradiation, similar to that reported previously after gamma irradiation. The extent of inhibition was not significantly greater in control cells, contrary to that seen with gamma rays. In time-course experiments a significant difference in degree of inhibition of DNA synthesis was observed between the cell types. Low doses of fast neutrons induced a G2-phase delay in both cell types, but the degree and extent of this delay was greater in ataxia-telangiectasia cells as observed previously with low-LET radiation.

Ataxia Telangiectasia↗