Heavy-Ion Effects on Mammalian Cells: Inactivation Measurements with Different Cell Lines

Wulf, Hans Christian; Kraft-Weyrather, W.; Miltenburger, H.G.; Blakely, Eleanor A.; Tobias, Cornelius A.; Kraft, Gerhard

doi:10.2307/3576639

Cited by 88 publications

(28 citation statements)

References 5 publications

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“…The cross-section and RBE for cell inactivation are comparable to those published elsewhere for mammalian cells exposed to Ar particles at comparable LETs (Wulf et al 1985;Blakely 1992;Courdi et al 1993). The crosssection for MN induction was almost half that for cell inactivation, respectively, 1/6 and 1/3 of the nuclear area of CAL4, suggesting that some particle traversals through the cell nucleus may not be sufficient for MN induction or cell killing.…”

Section: Discussionsupporting

confidence: 66%

Micronucleus induction and reproductive death in a human cell line exposed to low-energy argon beam

Courdi

Mari

Hérault

et al. 1995

Radiat Environ Biophys

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Little is known about the action of charged particles of very high linear energy transfer (LET) on human cells and, in particular, the relationship between DNA damage and reproductive death. The aim of this study was to measure the biological efficiency of a low-energy argon beam (E = 7.1 MeV/nucleon, LET = 1590 keV/micron) produced at GSI, Darmstadt, on a human melanoma cell line (CAL4) established in our Institute. Two different methods were used: the micronucleus (MN) test and the colony-forming assay. The MN test, using the cytochalasin-block method, is a measure of genotoxic damage. MN are scored in binucleate cells (BNC) and are formed from acentric fragments or whole chromosomes that have not been incorporated into daughter nuclei at mitosis. The colony-forming assay quantifies reproductive death. Parallel experiments were run with cobalt gamma-rays for comparison. After Co irradiation, the MN-free BNC dose-response curve coincided with that of the loss of colony-forming ability, suggesting the potential of the former as a predictive test of cell killing. After Ar irradiation, there was a dissociation between the two effects, especially at high doses: cell death was greater than the frequency of BNC with MN. The inactivation cross-section was 74 microns2; it was 39 microns2 for MN yield. Therefore, the relative biological effectiveness (RBE) was higher for cell killing than for MN yield (0.8 and 0.5, respectively at a Co dose of 3 Gy). The total MN count in BNC followed the same pattern of response as the fraction of BNC with MN.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 66%

Micronucleus induction and reproductive death in a human cell line exposed to low-energy argon beam

Courdi

Mari

Hérault

et al. 1995

Radiat Environ Biophys

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“…This quantification is based on a biophysical model, which combines information from the photon dose-response curve, the microscopic energy-deposition pattern in the ion tracks, and the size of the cell nucleus as a critical target [7]. The model has been tested in a number of in vitro studies [6,8], but only limited information is available from animal experiments on tumours and normal tissues [9,10,11]. The present study was, accordingly, initiated to supply such information.…”

Section: Introductionmentioning

confidence: 99%

Response of pig lung to irradiation with accelerated 12 C-ions

Dörr

Alheit

Appold

et al. 1999

Radiation and Environmental Biophysics

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The response of pig lungs to irradiation with 12C-ions was assessed in two experiments to validate the procedures for heavy ion therapy planning at the Gesellschaft für Schwerionenforschung (GSI) and to explore their range of applicability. In both experiments, the target volume (spread-out Bragg peak, SOBP) was planned to be a 4 cm long cylinder with a diameter of 4 cm. Doses in the SOBP were prescribed to be equivalent to 5x4 Gy, 5x5.5 Gy and 5x7 Gy of x-rays in the first experiment, and to 5 fractions of 7 Gy and 9 Gy in the second experiment. The lung response in the first experiment was less than expected on the basis of earlier experiments with photons. Pneumonitis reaction and chronic fibrotic changes were observed outside the prescribed high-dose region. In the second experiment, the effects were more pronounced than had been expected on the basis of the first experiment. Changes were most intense in the high-dose region, but were also seen throughout the lung along the beam channel. Moreover, significant skin reactions were observed at the beam entrance site in all animals and - less pronounced - at the beam exit site in 3 of the 6 animals. In conclusion, the complex irradiation geometry of the pig lung, the changes of body weight between the two experiments, and insufficient accounting for a change in the relative biological effectiveness (RBE) computation led to substantial deviations of the observed reactions from expectations, the reasons for which could be identified in a subsequent analysis. The less pronounced lung reaction in the first experiment was due to an overestimation of RBE in a preliminary version of the algorithm for its determination. The extension of the fibrotic reaction resulted from the smear-out of the high-dose region due to density variations in tissue structures, respiratory movement, and limited positioning accuracy. The skin reactions at the entrance port reflect the different treatment geometry in the two experiments. The one unexplained observation is the mild skin reaction that was observed in the second experiment at the beam exit site.

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“…Although the 235U fission fragments deposit an average of -28 times more energy per am (measured in keV/pm or linear energy transfer), their effectiveness is not greater by this factor because at some level a cell is killed; further energy deposition is then of no value. Measurements using heavy-ion accelerators impinging on cells have yielded some data on the effectiveness of high linear energy transfer particles in killing cells (9). The average cell inactivation cross section for the 235U fission products is =2.4 times greater than that for the 10B fragments.…”

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confidence: 99%

Uranium-loaded apoferritin with antibodies attached: molecular design for uranium neutron-capture therapy.

Hainfeld

1992

Proc. Natl. Acad. Sci. U.S.A.

116

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A method is described to deliver 2MU to tumors; the isotope would then be fissioned by incident neutrons, producing localized lethal radiation sufficient for therapy. Apoferritin was loaded with an average of =400 2mU atoms per molecule. Stability of the loaded apoferritin in solution was improved, so that only 8% loss of uranium occurred after 8 days at pH 7. Fab' antibody fragments were covalently attached to the uranium-loaded apoferritin, and the immunoreactivity of the conjugate was 92% of that for antibody alone. Such bio-uranium constructions should provide significant advantages over boronated antibodies to meet the requirements for clinical neutron-capture therapy.Neutron capture is a promising methodology for cancer therapy. Boron is the usual element used, but a system using uranium, as described here, may have significant advantages. Boron neutron-capture therapy is based upon localizing 10B in a tumor and irradiation with slow neutrons (1). Upon neutron absorption, 10B disintegrates to 7Li and an a particle, and these ionizing particles can kill cells. Three approaches have been used in boron neutron-capture therapy: (i) use of boron compounds that localize in tumors (2); (ii) use ofboron compounds that have specific metabolic uptake in tumor cells (3); and (iii) use of boron coupled to anti-tumor antibodies. Based upon antibody sites per tumor cell (105-106) and the concentration of boron necessary for therapy (>15 ppm), it has been estimated that 41000 boron atoms per antibody are required (4). This result has been difficult to achieve, and although recent progress has been made (5), no in vivo localization of the required amount of 10B has been demonstrated. Studies have shown that solid carcinomas exhibit a heterogeneous pattern of antibody distribution (different amounts of antibodies on different cells), have variable vascularity that could limit antibody uptake (6), and show poor penetration of antibodies beyond a few cell layers (7). Because the a and Li particles have a range ofonly about one cell, delivery of boron may be insufficient to many tumor cells.To circumvent some of the problems with boron, uranium may be used instead; this was proposed some 51 yr ago (8).235U has a neutron fission cross section that is 6.6 times lower than the 10B neutron-capture cross section (Table 1). However, a slow neutron splits the nucleus to two heavy charged ions producing 200 MeV, which is 71.4 times greater than the 10B breakup energy. The fission fragments of 235U have a longer range, giving a volume advantage of -8.4 over 10B.Another factor is the effectiveness of these particles in sterilizing cells. Although the 235U fission fragments deposit an average of -28 times more energy per am (measured in keV/pm or linear energy transfer), their effectiveness is not greater by this factor because at some level a cell is killed; further energy deposition is then of no value. Measurements using heavy-ion accelerators impinging on cells have yielded some data on the effectiveness of high linear energ...

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Heavy-Ion Effects on Mammalian Cells: Inactivation Measurements with Different Cell Lines

Cited by 88 publications

References 5 publications

Micronucleus induction and reproductive death in a human cell line exposed to low-energy argon beam

Micronucleus induction and reproductive death in a human cell line exposed to low-energy argon beam

Response of pig lung to irradiation with accelerated 12 C-ions

Uranium-loaded apoferritin with antibodies attached: molecular design for uranium neutron-capture therapy.

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