Papers by Eleanor Blakely
Cancer, Oct 11, 2018
To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the... more To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials (median, 47 participants) involving CIRT identified from the US clinicaltrials.gov trial registry and the World Health Organization International Clinical Trials Platform Registry. The objectives were to evaluate the potential for these trials to define the role of this modality in the treatment of specific cancer types and identify the major challenges and opportunities to advance this technology. A significant body of literature suggested the potential for advantageous dose distributions and, in preclinical biologic studies, the enhanced effectiveness for CIRT compared with photons and protons. In addition, clinical evidence from phase I/II trials, although limited, indicated the potential for CIRT to improve cancer outcomes. However, current high-level phase III randomized clinical trial evidence does not exist. Although there has been an increase in the number of trials investigating CIRT since 2010, and the number of countries and sites offering CIRT is slowly growing, this progress has excluded other countries. Several recommendations are proposed to study this modality to accelerate progress in the field, including: 1) increasing the number of multinational randomized clinical trials, 2) leveraging the existing CIRT facilities to launch larger multinational trials directed at common cancers combined with high-level quality assurance; and 3) developing more compact and less expensive next-generation treatment systems integrated with radiobiologic research and preclinical testing.
Protein Synthesis Modulates the Biological Effectiveness of the Combined Action of Hyperthermia and High-LET Radiation
Radiation Research, Mar 1, 1992
The combined effects of heavy-ion radiation and hyperthermia on the survival of CHO-SC1 cells and... more The combined effects of heavy-ion radiation and hyperthermia on the survival of CHO-SC1 cells and its temperature-sensitive (ts) mutant tsH1 cells were studied using accelerated neon ions followed by mild heating at 41.5 degrees C. The sequence of application of heat and high-LET radiation is significant to cell-killing effects. Heat applied to cells prior to irradiation with neon plateau ions (LET = 32 keV/microns) was less effective than heat applied immediately after irradiation. The ability of cells to synthesize new proteins plays a key role in this sequence-dependent thermal sensitization. When protein synthesis was shut down in tsH1 cells, the thermal enhancement of cell killing by high-LET radiation was the same regardless of the sequence. The thermal enhancement of radiation-induced cell killing was LET-dependent for the SC1 cells, but this was not clearly demonstrated in the tsH1 cells. Furthermore, the RBE of heated SC1 cells varied with LET and reached a maximum of greater than 3 at 80 keV/microns. In the absence of protein synthesis, the maximum RBE value was reduced to 2.6. These results suggest that the accumulation of cellular damage caused by exposure to densely ionizing particles with increasing LETs can be potentiated with active protein synthesis during postirradiation heat treatment.
HZE effects on mammalian cells
Advances in Space Research, 1984
In track segment experiments cell survival and chromosome aberrations of mammalian cells have bee... more In track segment experiments cell survival and chromosome aberrations of mammalian cells have been measured for various heavy ion beams between helium and uranium in the energy range between 0.5 and 960 MeV/u, corresponding to a velocity range of 0.03 to 0.87 C, and an LET spectrum from 10 to 15 000 keV/micrometers. At low LET, the cross section (sigma) for cell killing increases with increasing LET and shows a common curve for all ions regardless of the atomic number. This indicates that in this region the track structure of the different ions is of only a minor influence, and it is rather the total energy transfer, which is important for cell killing. At higher LET values, deviations from a common sigma-LET curve can be observed which indicate a saturation effect. The saturation of the lighter ions occurs at lower LET values than for the heavier ions. These findings are also confirmed by the chromosome data, where the efficiency for the induction of chromosomal aberrations for high LET particles depends on the track structure and is nearly independent of LET. In the heavier beams (Z > or = 10) individual particles cause multiple chromosome breaks in mitotic cells.
Repair and misrepair of heavy-ion-induced chromosomal damage
Advances in Space Research, 1989
The premature chromosome condensation (PCC) technique was used to investigate chromosomal damage,... more The premature chromosome condensation (PCC) technique was used to investigate chromosomal damage, repair, and misrepair in the G phase of a human/hamster hybrid cell line that contains a single human chromosome. Plateau-phase cell cultures were exposed to either x-rays or a 425 MeV/u beam of neon ions near the Bragg peak where the LET is 183 kev/micrometers. An in situ hybridization technique coupled to fluorescent staining of PCC spreads confirmed the linearity of the dose response for initial chromatin breakage in the human chromosome to high doses (1600 cGy x-ray or 1062 cGy Ne). On Giemsa-stained slides, initial chromatin breakage in the total genome and the rejoining kinetics of these breaks were determined. As a measure of chromosomal misrepair, ring PCC aberrations were also scored. Ne ions were about 1.5 x more effective per unit dose compared to x-rays at producing the initially measured chromatin breakage. 90% of the x-ray-induced breaks rejoined in cells incubated at 37 degrees C after exposure. In contrast, only 50% of Ne-ion-induced breaks rejoined. In the irradiated G1 cells, ring PCC aberrations increased with time apparently by first order kinetics after either x-ray or Ne exposures. However, far fewer rings formed in Ne-irradiated cells after a dose giving a comparable initial number of chromatin breaks. Following x-ray exposures, the yield of rings formed after long repair times (6 to 9 hrs) fit a quadratic dose-response curve. These results indicate quantitative and qualitative differences in the chromosomal lesions induced by low- and high-LET radiations.
Current approaches to evaluate space radiation health risks and mitigation
cosp, Jul 1, 2018
Preclinical Radiobiology and Predictive Assays
Biological and medical physics series, Sep 6, 2011
ABSTRACT Physical measurements of absorbed particle radiation doses are currently inadequate to e... more ABSTRACT Physical measurements of absorbed particle radiation doses are currently inadequate to estimate biological outcome at the stopping ranges of particle beams from protons to heavier ions. Estimates of biological significance and clinical impact are essential additional elements to implement ion beam therapy (IBT). This chapter provides a brief review of the current status of preclinical molecular and cellular radiobiology and predictive assays with a focus on the current use of radiobiology to characterize radiation fields of ions, to implement treatment planning with scanned ion beams, and to predict successful clinical outcome.
PubMed, Jun 1, 1978
Stationary-phase populations of Chinese hamster V-79 cells were irradiated with 250 kV X-rays and... more Stationary-phase populations of Chinese hamster V-79 cells were irradiated with 250 kV X-rays and the Bragg peaks (spread to a width of 4 cm) of energetic He-, C-, Ne-, and A-ion beams produced at the 184-inch cyclotron and BEVALAC at Lawrence Berkeley Laboratory. Survival curves were generated with each radiation for cells suspended in air-saturated and nitrogen-saturated medium with and without sensitizer present. The oxygen enhancement ratios (OERs) measured for X-rays with 1mM metronidazole and 0.5 mM misonidazole were 2.0 and 1.6 respectively. The OERs without sensitizer for He-, C-, Ne-, and A-ion Bragg peaks were 2.4, 1.7, 1.6 and 1.4 respectively. For each type of radiation tested the presence of hypoxic-cell sensitizers resulted in an additional reduction in the measured OERs, indicating that these drugs should be of benefit in the radiotherapy planned with these and other high LET radiations.
New measurements for hadrontherapy and space radiation: biology
PubMed, 2001
The dual goals of optimizing clinical efficacy of hadrontherapy and determining radiation risk es... more The dual goals of optimizing clinical efficacy of hadrontherapy and determining radiation risk estimates for space research have intersected to a common focus for investigation of the biological effects of charged particles. This paper briefly highlights recent international progress at accelerator facilities engaged in both biological and clinical studies of the effects of particle beams, primarily protons, carbon and iron ions. Basic mechanisms of molecular, cellular and tissue responses continue under investigation for radiations with a range of ionization densities. Late normal tissue effects, including the risk of cancer in particular, are of importance for both research fields. International cooperation has enhanced the rate of progress as evidenced by recent publications. Specific areas of biomedical research related to the biological radiotoxicity of critical organs (especially the central nervous system), individual radiosensitivities to radiation carcinogenesis, and the analysis of effects in mixed radiation fields still require more research. Recommendations for addressing these issues are made.
Survival and Kinetic Response of V79-spheroids after Exposure to Heavy Ion Beams
International Journal Of Radiation Biology, 1980
Multicellular V79-spheroids and V79-monolayer cultures were irradiated with charged particle beam... more Multicellular V79-spheroids and V79-monolayer cultures were irradiated with charged particle beams. The beams studied and their initial extraction energies were carbon (400 MeV/amu), neon (425 MeV/amu) and argon (570 MeV/amu). Survival was measured at a position in the plateau, and at a position in the middle of a 4 cm extended Bragg peak. Relative biological efficiency (r.b.e.) values for survival of spheroid cells at peak positions were high (4.1--4.2) in comparison to those obtained with monolayer cultures (1.8--2.4) of the same cell line. This finding is explained by the fact that three dimensional cell contact, which benefits survival after low LET radiation, does not influence survival after heavy ion irradiations in the Bragg peak. The peak-plateau r.b.e.-ratio was most advantageous for the carbon-ion beam (= 4.2). Whereas non-cycling inner spheroid cells showed hardly any kinetic changes up to 24 hours after heavy ion irradiation, outer cycling spheroid cells were arrested in G2 + M within a few hours after exposure.
Responses of synchronous L5178Y S/S cells to heavy ions and their significance for radiobiological theory
Proceedings of the Royal Society of London, Jun 22, 1989
Synchronous suspensions of the radiosensitive S/S variant of the L5178Y murine leukaemic lymphobl... more Synchronous suspensions of the radiosensitive S/S variant of the L5178Y murine leukaemic lymphoblast at different positions in the cell cycle were exposed aerobically to segments of heavy-ion beams ( 20 Ne, 28 Si, 40 Ar, 56 Fe and 93 Nb) in the Bragg plateau regions of energy deposition. The incident energies of the ion beams were in the range of 460 ± 95 MeV u -1 , and the calculated values of linear energy transfer (LET ∞ ) for the primary nuclei in the irradiated samples were 33 ± 3, 60 ± 3, 95 ± 5, 213 ± 21 and 478 ± 36 keV μm -1 , respectively; 280 kVp X-rays were used as the baseline radiation. Generally, the maxima or inflections in relations between relative biological effectiveness (RBE) and LET ∞ were dependent upon the cycle position at which the cells were irradiated. Certain of those relations were influenced by post-irradiation hypothermia. Irradiation in the cell cycle at mid -G 1 to mid-G 1 +3 h, henceforth called G 1 to G 1 + 3 h, resulted in survival curves that were close approximations to simple exponential functions. As the LET ∞ was increased, the RBE did not exceed 1.0, and by 478 keV μm -1 it had fallen to 0.39. Although similar behaviour has been reported for inactivation of proteins and certain viruses by ionizing radiations, so far the response of the S/S variant is unique for mammalian cells. The slope of the survival curve for X-photons ( D 0 :0.27 Gy) is reduced in G 1 to G 1 + 3 h by post-irradiation incubation at hypothermic temperatures and reaches a minimum ( D 0 : 0.51 Gy) at 25 °C. As the LET ∞ was increased, however, the extent of hypothermic recovery was reduced progressively and essentially was eliminated at 478 keV μm -1 . At the cycle position where the peak of radioresistance to X-photons occurs for S/S cells, G 1 + Sh, increases in LET ∞ elicited only small increases in RBE (at 10% survival), until a maximum was reached around 200 keV μm -1 . At 478 keV μm -1 , what little remained of the variation in response through the cell cycle could be attributed to secondary radiations (δ rays) and smaller nuclei produced by fragmentation of the primary ions. Definitions 1. Linear energy transfer (LET ∞ ) is the energy deposited per unit length of track by an ionizing particle and usually is measured in kiloelectron volts per micrometer (in water). 2. Penumbra . Atomic interactions along the track of a heavy ion result in the ejection of electrons with energies sufficient to move beyond the region of dense ionization which constitutes the track core, and so may be considered to form a penumbra of sparsely ionizing radiations around the track core. 3. RBE . The effectiveness of a densely ionizing radiation (heavy ion) compared to a sparsely ionizing radiation, e. g. X- or γ -photons, is measured by the inverse ratio of the doses of each radiation needed to produce a given radiobiological effect, and is known as the relative biological effectiveness (RBE): the usual reference radiation is 250 kVp X-rays. 4. D 0 is a measure of the radiosensitivity of a cell as determined from the (limiting) linear slope of the survival curve, and is the dose in Gray (1 Gy ≡ 1 Joule kg -1 ) required to reduce the survival at a point anywhere in that region of the survival curve to 37% of its value at that point.
Life sciences in space research, Jul 1, 2015
Cancer is an important long-term risk for astronauts exposed to protons and high-energy charged p... more Cancer is an important long-term risk for astronauts exposed to protons and high-energy charged particles during travel and residence on asteroids, the moon, and other planets. NASA's Biomedical Critical Path Roadmap defines the carcinogenic risks of radiation exposure as one of four type I risks. A type I risk represents a demonstrated, serious problem with no countermeasure concepts, and may be a potential "show-stopper" for long duration spaceflight. Estimating the carcinogenic risks for humans who will be exposed to heavy ions during deep space exploration has very large uncertainties at present. There are no human data that address risk from extended exposure to complex radiation fields. The overarching goal in this area to improve risk modeling is to provide biological insight and mechanistic analysis of radiation quality effects on carcinogenesis. Understanding mechanisms will provide routes to modeling and predicting risk and designing countermeasures. This white paper reviews broad issues related to experimental models and concepts in space radiation carcinogenesis as well as the current state of the field to place into context recent findings and concepts derived from the NASA Space Radiation Program.
Heavy-Ion Effects on Mammalian Cells: Inactivation Measurements with Different Cell Lines
Radiation Research, Nov 1, 1985
In track segment experiments, the inactivation of different mammalian cells by heavy charged part... more In track segment experiments, the inactivation of different mammalian cells by heavy charged particles between helium and uranium in the energy range between 1 and 1000 MeV/u has been measured at the heavy ion accelerator Unilac, Darmstadt, the Tandem Van de Graaf, Heidelberg, and the Bevalac, Berkeley. The inactivation cross sections calculated from the final slope of the dose-effect curves are given as a function of the particle energy and the linear energy transfer.
Radiation Research, Nov 22, 2016
Complex mixed radiation fields exist in interplanetary space, and little is known about their lat... more Complex mixed radiation fields exist in interplanetary space, and little is known about their late effects on space travelers. In silico synergy analysis default predictions are useful when planning relevant mixed-ion-beam experiments and interpreting their results. These predictions are based on individual dose-effect relationships (IDER) for each component of the mixed-ion beam, assuming no synergy or antagonism. For example, a default hypothesis of simple effect additivity has often been used throughout the study of biology. However, for more than a century pharmacologists interested in mixtures of therapeutic drugs have analyzed conceptual, mathematical and practical questions similar to those that arise when analyzing mixed radiation fields, and have shown that simple effect additivity often gives unreasonable predictions when the IDER are curvilinear. Various alternatives to simple effect additivity proposed in radiobiology, pharmacometrics, toxicology and other fields are also known to have important limitations. In this work, we analyze upcoming murine Harderian gland (HG) tumor prevalence mixed-beam experiments, using customized open-source software and published IDER from past single-ion experiments. The upcoming experiments will use acute irradiation and the mixed beam will include components of high atomic number and energy (HZE). We introduce a new alternative to simple effect additivity, ''incremental effect additivity'', which is more suitable for the HG analysis and perhaps for other end points. We use incremental effect additivity to calculate default predictions for mixture dose-effect relationships, including 95% confidence intervals. We have drawn three main conclusions from this work. 1. It is important to supplement mixed-beam experiments with single-ion experiments, with matching end point(s), shielding and dose timing. 2. For HG tumorigenesis due to a mixed beam, simple effect additivity and incremental effect additivity sometimes give default predictions that are numerically close. However, if nontargeted effects are important and the mixed beam includes a number of different HZE components, simple effect additivity becomes unusable and another method is needed such as incremental effect additivity. 3. Eventually, synergy analysis default predictions of the effects of mixed radiation fields will be replaced by more mechanistic, biophysically-based predictions. However, optimizing synergy analyses is an important first step. If mixed-beam experiments indicate little synergy or antagonism, plans by NASA for further experiments and possible missions beyond low earth orbit will be substantially simplified.
Sequential Exposures of Mammalian Cells to Low- and High-LET Radiations: II. As a Function of Cell-Cycle Stages
Radiation Research, Jul 1, 1988
The synergistic effects of low- and high-LET radiations were further studied with partially synch... more The synergistic effects of low- and high-LET radiations were further studied with partially synchronized Chinese hamster V79 cells. Principally, nearly monoenergetic 425 MeV/u neon ions and 570 MeV/u argon ions produced near the Bragg peak were employed as the high-LET radiations and 225 kVp X rays as the low-LET counterpart. It was found that the killing effect due to damage interaction after sequential irradiations with the particle beam and X rays varies throughout the cell cycle. The greatest effect was observed in late-S phase which was most resistant to either of the radiations. The effect was quantitatively less in the G1/S border and in G2. Effects on pure mitotic cells have not been investigated in this study. For all cell stages studied, a dose of high-LET particles modified the shape of the X-ray survival curve in a way similar to the modification predicted by an appropriately selected X-ray dose. This finding suggests that the mechanism for the synergistic effects is similar to that operating for sequential treatments with X rays alone. Experiments with an S population, either incubated at 37 degrees C or room temperature between fractionation of high- and low-LET radiation treatments further verified that the damage involved is a repairable type. At a certain fractionation interval (6 to 8 h) following a dose of high-LET treatment, initially asynchronous cells were found to be very sensitive to X-irradiation. It is noteworthy that the net killing measured at this "radiosensitive window" was as effective as the killing observed by "immediately" sequential treatments with the same doses of high- and low-LET radiations. Such a time window also existed when the order of the treatment sequence was reversed except that the time of occurrence was earlier and the window was broader. This sensitization effect may be explained by radiation-induced G2 arrest together with an increase of radiosensitivity as the previously irradiated cells progress into S phase. Radiotherapy strategies using combined high-LET and low-LET radiations for rapidly proliferative tumors are presented.
Radiation Biophysical Studies with Mammalian Cells and a Modulated Carbon Ion Beam
Radiation Research, Apr 1, 1978
... 5. KK Fu and TL PHILLIPS, The RBE and OER of neon ions for the EMT-6 tumor. Radiology 120, 43... more ... 5. KK Fu and TL PHILLIPS, The RBE and OER of neon ions for the EMT-6 tumor. Radiology 120, 439-441 (1976). 6. EA BLAKELY, TCH YANG, JT LYMAN, A. CHATTERJEE, and CA TOBIAS, Survival of human kidney cells and oxygen effect in oxygen, neon, and argon beams. ...
Chromosomal Damage and Repair in G 1 -Phase Chinese Hamster Ovary Cells Exposed to Charged-Particle Beams
Radiation Research, Jun 1, 1994
Chromosomal fragmentation was examined in G1-phase Chinese hamster ovary cells using the prematur... more Chromosomal fragmentation was examined in G1-phase Chinese hamster ovary cells using the premature chromosome condensation (PCC) technique. The yield and distribution of chromatin breaks, the lesions revealed by PCC, were measured in cells exposed to X rays or each of nine particle beams covering a range of LET from 0.56 to 2700 keV/microns. The average number of breaks per cell was found to be linearly proportional to the fluence of high-LET neon ions (183 keV/microns). Assuming a linear response for the other beams, the level of breakage per unit dose rose from a plateau at the lowest LET values to a peak in the 100-200 keV/microns range and then declined continuously thereafter, eventually falling well below the low-LET plateau. The maximum breakage RBE was 1.5. The average number of breaks per particle traversal rose steadily from 0.006 to 11 breaks/cell as the LET increased from 0.56 to 2700 keV/microns. The breaks were distributed randomly within the cell population after low-LET irradiation, but became progressively over-dispersed with increasing LET. Rejoining of prematurely condensed chromosomes plus fragments was followed for up to 5 h for four particle beams having LET values between 0.56 and 183 keV/microns. An LET-dependent trend toward higher levels of residual fragments was observed.
Drastic G 2 Arrest in Mammalian Cells after Irradiation with Heavy-Ion Beams
Radiation Research, Jul 1, 1979
... CHRISTINE LCKE-HUHLE,* ELEANOR A. BLAKELY, POLLY Y. CHANG, AND CORNELIUS A. TOBIAS Lawrence B... more ... CHRISTINE LCKE-HUHLE,* ELEANOR A. BLAKELY, POLLY Y. CHANG, AND CORNELIUS A. TOBIAS Lawrence Berkeley Laboratory, University of California ... more effective in causing a G2 + M block, measured by the method of flow microfluorometry, than low-LET radiation. ...
Heavy ion-induced chromosomal damage and repair
Advances in Space Research, 1992
We have been using the "premature chromosome condensation (PCC)" technique to i... more We have been using the "premature chromosome condensation (PCC)" technique to investigate chromosomal breakage, rejoining and misrepair induced by accelerated heavy ions. With the presentation of new Fe experiments, we now review the available PCC data to summarize our current understanding of the action of high velocity charged particles on mammalian chromosomes. Implications for the survival RBE/LET relationship are also discussed.
Characterization of Hydroxyl Radical-induced Damage after Sparsely and Densely Ionizing Irradiation
International Journal Of Radiation Biology, 1985
The extent of hydroxyl radical mediated cell inactivation was measured for a variety of particle ... more The extent of hydroxyl radical mediated cell inactivation was measured for a variety of particle beams ranging from 8.5 Me V/u neon ions to 570 Me V/u argon ions. In general, the fraction of the total radiosensitivity caused by OH decreases from close to 60 per cent at low ionization density or low linear energy transfer (low LET) to close to 25 per cent at high LET for aerobically irradiated mammalian cells. The extent of OH induced cell lethality can be explained in terms of LET infinity only for low energy or low atomic number particles where fragmentations and complicated track structures do not contaminate the characteristic particle LET. For example, at a calculated LET infinity of 100 ke V/micron, the OH mediated fraction of the total radiation damage is about 25 per cent for low energy carbon but close to 40 per cent for high energy carbon ions. For low energy charged nuclei of approximately the same energy, as the 5.4-13.4 MeV/u He, Li, C and Ne ions in this report, there is a predictable diminution of the OH mediated effect with increasing LET infinity; however, the biological effect cannot be predicted accurately from calculated LET infinity values for high energy particle irradiation, nor indeed from a variety of low energy charged particles of quite different energies (incident velocities). This illustrates the unsuitability of using LET as a unifying parameter, except under specific circumstances. As more is learned about the energy deposition for energized charged particles in terms of track structure (core and penumbra), it may be possible to characterize the radiobiological data with a better physical parameter than LET infinity.
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Papers by Eleanor Blakely