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Time dependence of relative biological effectiveness (RBE) of carbon ions for skin damage was investigated to answer the question of whether the flat distribution of biological doses within a Spread-Out Bragg peak (SOBP) which is designed based on in vitro cell kill could also be flat for in vivo late responding tissue. Two spots of Indian ink intracutaneously injected into the legs of C3H mice were measured by calipers. An equieffective dose to produce 30% skin contraction was calculated from a dose–response curve and used to calculate the RBE of carbon ion beams. We discovered skin contraction progressed after irradiation and then reached a stable/slow progression phase. Equieffective doses decreased with time and the decrease was most prominent for gamma rays and least prominent for 100 keV/μm carbon ions. Survival parameter of alpha but not beta in the linear-quadratic model is closely related to the RBE of carbon ions. Biological doses within the SOBP increased with time but their distribution was still flat up to 1 year after irradiation. The outcomes of skin contraction studies suggest that (i) despite the higher RBE for skin contracture after carbon ions compared to gamma rays, gamma rays can result in a more severe late effect of skin contracture. This is due to the carbon effect saturating at a lower dose than gamma rays, and (ii) the biological dose distribution throughout the SOBP remains approximately the same even one year after exposure. [ABSTRACT FROM AUTHOR]

The goal of this work was to clarify the effect of carbon-ion beams on reduction of the metastatic potential of malignant melanoma using in vitro and in vivo techniques. We utilized a 290 MeV/u carbon beam with a 6-cm spread-out Bragg-peak (SOBP), 137Cs γ rays or 200 kVp X rays for irradiation, and in vitro murine melanoma B16/BL6 cells that were implanted into C57BL/6J mice. The metastatic abilities (migration, invasion and adhesion) were suppressed by carbon ion treatment at all doses that were tested, whereas invasion and migration tended to increase after X-ray irradiation at low dose. Biological effects of carbon ions increased with linear energy transfer (LET) for both cell killing and metastatic abilities, although the effects were more pronounced for migration and invasion. mRNA expression of E-cadherin was significantly downregulated with low-dose photon exposures, but increased with dose or LET. Expression of Mel-CAM and L1-CAM was upregulated after low-dose photon exposure, but decreased with dose, especially after carbon-ion treatment. Conversely, these molecules showed a reversal in expression changes, especially after low-dose photon exposure. Cell-cell adhesion may be an important contributor to the antimetastatic effect of carbon ion treatment. The number of lung metastases after local tumor irradiation significantly decreased with increased dose and LET, with carbon ions being more effective than γ rays. Integrating dose-response curves to examine the relationship between cell killing and lung metastasis clearly showed that carbon ions inhibit lung metastasis more efficiently than photons at the iso-effective level of cell killing. Thus, carbon ions were more effective than photon beams, not only at killing tumor cells, but also at inhibiting metastatic spread caused by tumor cells that survived irradiation. [ABSTRACT FROM AUTHOR]

Purpose: To determine the dose-dependent relative biological effectiveness (RBE) for tumor prevalence in mice receiving single localized doses to their right leg of either carbon ions (15, 45 or 75 keV/μm) or 137Cs gamma rays. Methods and materials: A total of 1647 female C3H mice were irradiated to their hind legs with a localized dose of either reference gamma rays or 15, 45 or 75 keV/μm carbon-ion beams. Irradiated mice were evaluated for tumors twice a month during their three-year life span, and the dimensions of any tumors found were measured with a caliper. The tumor induction frequency was calculated by Kaplan-Meier analysis. Results: The incidence of tumors from 50 Gy of 45 keV/μm carbon ions was marginally higher than those from 50 Gy of gamma rays. However, 60 Gy of 15 keV/μm carbon ions induced significantly fewer tumors than did gamma rays. RBE values of 0.87 + 0.12, 1.29 + 0.08 or 2.06 + 0.39 for lifetime tumorigenesis were calculated for 15, 45 or 75 keV/μm carbon-ion beams, respectively. Fibrosarcoma predominated, with no Linear Energy Transfer (LET)-dependent differences in the tumor histology. Experiments measuring the late effect of leg skin shrinkage suggested that the carcinogenic damage of 15 keV/μm carbon ions would be less than that of gamma rays. Conclusions: We conclude that patients receiving radiation doses to their normal tissues would face less risk of secondary tumor induction by carbon ions of intermediate LET values compared to equivalent doses of photons. [ABSTRACT FROM AUTHOR]

Purpose: To compare the biological effectiveness of 290 MeV/amu carbon-ion beams in Chiba, Japan and in Darmstadt, Germany, given that different methods for beam delivery are used for each. Methods and Materials: Murine small intestine and human salivary gland tumor (HSG) cells exponentially growing in vitro were irradiated with 6-cm width of spread-out Bragg peaks (SOBPs) adjusted to achieve nearly identical beam depth–dose profiles at the Heavy-Ion Medical Accelerator in Chiba, and the SchwerIonen Synchrotron in Darmstadt. Cell kill efficiencies of carbon ions were measured by colony formation for HSG cells and jejunum crypts survival in mice. Cobalt-60 γ rays were used as the reference radiation. Isoeffective doses at given survivals were used for relative biological effectiveness (RBE) calculations and interinstitutional comparisons. Results: Isoeffective D10 doses (mean ± standard deviation) of HSG cells ranged from 2.37 ± 0.14 Gy to 3.47 ± 0.19 Gy for Chiba and from 2.31 ± 0.11 Gy to 3.66 ± 0.17 Gy for Darmstadt. Isoeffective D10 doses of gut crypts after single doses ranged from 8.25 ± 0.17 Gy to 10.32 ± 0.14 Gy for Chiba and from 8.27 ± 0.10 Gy to 10.27 ± 0.27 Gy for Darmstadt, whereas isoeffective D30 doses after three fractionated doses were 9.89 ± 0.17 Gy through 13.70 ± 0.54 Gy and 10.14 ± 0.20 Gy through 13.30 ± 0.41 Gy for Chiba and Darmstadt, respectively. Overall difference of RBE between the two facilities was 0–5% or 3–7% for gut crypt survival or HSG cell kill, respectively. Conclusion: The carbon-ion beams at the National Institute of Radiological Sciences in Chiba, Japan and the Gesellschaft für Schwerionenforschung in Darmstadt, Germany are biologically identical after single and daily fractionated irradiation. [Copyright &y& Elsevier]

Background and purpose Carbon-ion radiotherapy uses spread-out Bragg peaks (SOBP) to produce uniform biological effects within a target volume. The relative biological effectiveness is determined by the in vitro cell kill after a single dose is employed to design the SOBP. A question remains as to whether biological effects for in vivo tissues after fractionated doses are also uniform within the SOBP. Material and methods Mouse foot skin was irradiated with fractionated doses of carbon ions at various linear energy transfer (LET) values. A new ridge filter was designed based on alpha and beta values for each LET to cause moderate skin reaction, and was studied concerning its uniformity. Results The reciprocal total doses of intermediate-LET carbon ions and of reference gamma rays linearly increased with an increase of a dose per fraction in Fe-plots. As the single total dose of higher LET run off linearity, data obtained from 2 to 6 fractions were used to design a new ridge filter. The physical dose distribution of the new ridge filter was almost identical to, and indistinguishable from, the ridge filter designed based on the in vitro cell kill. Conclusions The LET dependence of alpha is a principle of the biological factor to be used for designing spread-out Bragg peaks of carbon-ion radiotherapy. [ABSTRACT FROM AUTHOR]

The aim of this study was to measure the RBE (relative biological effectiveness) and OER (oxygen enhancement ratio) for survival of cells within implanted solid tumors following exposure to 290MeV/nucleon carbon-ion beams or X-rays. Squamous cell carcinoma cells (SCCVII) were transplanted into the right hind legs of syngeneic C3H male mice. Irradiation with either carbon-ion beams with a 6-cm spread-out Bragg peak (SOBP, at 46 and 80keV/μm) or X-rays was delivered to 5-mm or less diameter tumors. We defined three different oxygen statuses of the irradiated cells. Hypoxic and normoxic conditions in tumors were produced by clamping or not clamping the leg to avoid blood flow. Furthermore, single-cell suspensions were prepared from non-irradiated tumors and directly used to determine the radiation response of aerobic cells. Single-cell suspensions (aerobic condition) were fully air-saturated. Single-cell suspensions were prepared from excised and trypsinized tumors, and were used for in vivo–in vitro colony formation assays to obtain cell survival curves. The RBE values increased with increasing LET in SOBP beams. The maximum RBE values in three different oxygen conditions; hypoxic tumor, normoxic tumor and aerobic cells, were 2.16, 1.76 and 1.66 at an LET of 80keV/μm, respectively. After X-ray irradiation the OERh/n values (hypoxic tumor/normoxic tumor) were lower than the OERh/a (hypoxic tumor/aerobic cells), and were 1.87±0.13 and 2.52±0.11, respectively. The OER values of carbon-ion irradiated samples were small in comparison to those of X-ray irradiated samples. However, no significant changes of the OER at proximal and distal positions within the SOBP carbon-ion beams were observed. To conclude, we found that the RBE values for cell survival increased with increasing LET and that the OER values changed little with increasing LET within the SOBP carbon-ion beams. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The response of 2-amino-4-([14C]methylthio)butyric acid ([14C]Met) uptake and [125I]3-iodo-alpha-methyl-l-tyrosine ([125I]IMT) uptake to radiotherapy of C10 glioma cells was compared to elucidate the intracellular reactions that affect the response of 2-amino-4-([11C]methylthio)butyric acid ([11C]Met) uptake to radiotherapy. Methods: After irradiation of cultured (3 Gy) or xenografted C10 glioma cells (25 Gy) using a carbon ion beam, the accumulation of [14C]Met and [125I]IMT in the tumors was investigated. The radiometabolites in xenografted tumors after radiotherapy were analyzed by size-exclusion HPLC. Results: [14C]Met provided earlier responses to the carbon ion beam irradiation than [125I]IMT in both cultured and xenografted tumors. While [125I]IMT remained intact in xenografted tumor before and after irradiation, the radioactivity derived from [14C]Met was observed both in high molecular fractions and intact fractions, and the former decreased after irradiation. Conclusion: The earlier response of [11C]Met uptake to tumor radiotherapy could be attributable to the decline in the intracellular energy-dependent reactions of tumors due to radiotherapy. [Copyright &y& Elsevier]