Helium ions for radiotherapy? Physical and biological verifications of a novel treatment modality

Purpose: Modern facilities for actively scanned ion beam radiotherapy allow in principle the use of helium beams, which could present specific advantages, especially for pediatric tumors. In order to assess the potential use of these beams for radiotherapy, i.e., to create realistic treatment plans, the authors set up a dedicated He-4 beam model, providing base data for their treatment planning system TRiP98, and they have reported that in this work together with its physical and biological validations. Methods: A semiempirical beam model for the physical depth dose deposition and the production of nuclear fragments was developed and introduced in TRiP98. For the biological effect calculations the last version of the local effect model was used. The model predictions were experimentally verified at the HIT facility. The primary beam attenuation and the characteristics of secondary charged particles at various depth in water were investigated using He-4 ion beams of 200 MeV/u. The nuclear charge of secondary fragments was identified using a Delta E/E telescope. 3D absorbed dose distributions were measured with pin point ionization chambers and the biological dosimetry experiments were realized irradiating a Chinese hamster ovary cells stack arranged in an extended target. Results: The few experimental data available on basic physical processes are reproduced by their beam model. The experimental verification of absorbed dose distributions in extended target volumes yields an overall agreement, with a slight underestimation of the lateral spread. Cell survival along a 4 cm extended target is reproduced with remarkable accuracy. Conclusions: The authors presented a simple simulation model for therapeutical He-4 beams which they introduced in TRiP98, and which is validated experimentally by means of physical and biological dosimetries. Thus, it is now possible to perform detailed treatment planning studies with He-4 beams, either exclusively or in combination with other ion modalities. (C) 2016 Author(s)

Influence of chronic hypoxia and radiation quality on cell survival.

To investigate the influence of chronic hypoxia and anoxia on cell survival after low- and high-LET radiation, CHO-K1 cells were kept for 24 h under chronic hypoxia (94.5% N2; 5% CO2; 0.5% O2) or chronic anoxia (95% N2; 5% CO2). Irradiation was performed using 250 kVp X-rays or carbon ions with a dose average LET of 100 keV/μm either directly under the chronic oxygenation states, or at different time points after reoxygenation. Moreover, the cell cycle distribution for cells irradiated under different chronic oxic states was measured over 24 h during reoxygenation. The measurements showed a fairly uniform cell cycle distribution under chronic hypoxia, similar to normoxic conditions. Chronic anoxia induced a block in G1 and a strong reduction of S-phase cells. A distribution similar to normoxic conditions was reached after 12 h of reoxygenation. CHO cells had a similar survival under both acute and chronic hypoxia. In contrast, survival after irradiation under chronic anoxia was slightly reduced compared to that under acute anoxia. We conclude that, in hamster cells, chronic anoxia is less effective than acute anoxia in inducing radioresistance for both X-rays and carbon ions, whereas in hypoxia, acute and chronic exposures have a similar impact on cell killing

Efficient Rejoining of DNA Double-Strand Breaks despite Increased Cell-Killing Effectiveness following Spread-Out Bragg Peak Carbon-Ion Irradiation

Radiotherapy of solid tumors with charged particles holds several advantages in comparison to photon therapy; among them conformal dose distribution in the tumor, improved sparing of tumor-surrounding healthy tissue, and an increased relative biological effectiveness (RBE) in the tumor target volume in the case of ions heavier than protons. A crucial factor of the biological effects is DNA damage, of which DNA double-strand breaks (DSBs) are the most deleterious. The reparability of these lesions determines the cell survival after irradiation and thus the RBE. Interestingly, using phosphorylated H2AX as a DSB marker, our data in human fibroblasts revealed that after therapy-relevant spread-out Bragg peak irradiation with carbon ions DSBs are very efficiently rejoined, despite an increased RBE for cell survival. This suggests that misrepair plays an important role in the increased RBE of heavy-ion radiation. Possible sources of erroneous repair will be discussed

The Effect of X-Ray and Heavy Ions Radiations on Chemotherapy Refractory Tumor Cells

Purpose: The purpose of this study is to link both numeric and structural chromosomal aberrations to the effectiveness of radiotherapy in chemotherapy refractory tumor cells. Materials and methods: Neuroblastoma (LAN-1) and 79HF6 glioblastoma cells derived from patients and their chemoresistant sublines were artificially cultured as neurospheres and irradiated by X-rays and heavy ions sources. All the cell lines were irradiated by Carbon-SIS with LET of 100 keV/μm. However, 79HF6 cells and LAN-1 cells were also irradiated by Carbon-UNILAC with LET of 168 keV/μm and Nickel ions with LET of 174 keV/μm, respectively. The effect of radiation on the survival and proliferation of cells was addressed by standard clonogenic assays. In order to analyze cell karyotype standard Giemsa staining, multicolor fluorescence in situ hybridization (mFISH) and multicolor banding (mBAND) techniques were applied. Results: Relative biological effectiveness values of heavy ion beams relative to X-rays at the D10 values were found between 2.3 and 2.6 with Carbon-SIS and Nickel for LAN-1 and between 2.5 and 3.4 with Carbon-SIS and Carbon-UNILAC for 79HF6 cells. Chemorefractory LAN-1RETO cells were found more radioresistant than untreated LAN-1WT cells. 79HF6RETO glioblastoma cells were found more radiosensitive than cytostatic sensitive cells 79HF6WT. Sphere formation assay showed that LAN-1RETO cells were able to form spheres in serum-free culture, whereas 79HF6 cells could not. Most of 79HF6WT cells revealed a number of 71–90 chromosomes, whereas 79HF6RETO revealed a number of 52–83 chromosomes. The majority of LAN-1WT cells revealed a number of 40–44 chromosomes. mFISH analysis showed some stable aberrations, especially on chromosome 10 as judged by the impossibility to label this region with specific probes. This was corroborated using mBAND analysis. Conclusion: Heavy ion irradiation was more effective than X-ray in both cytostatic naive cancer and chemoresistant cell lines. LAN-1RETO chemoresistant neuroblastoma cells were found to be more radioresistant than the cytostatic naive cells (LAN-1WT), whereas this effect was not found in 79HF6 cells

The Effect of X-Ray and Heavy Ions Radiations on Chemotherapy Refractory Tumor Cells

PURPOSE: The purpose of this study is to link both numeric and structural chromosomal aberrations to the effectiveness of radiotherapy in chemotherapy refractory tumor cells. MATERIALS AND METHODS: Neuroblastoma (LAN-1) and 79HF6 glioblastoma cells derived from patients and their chemoresistant sublines were artificially cultured as neurospheres and irradiated by X-rays and heavy ions sources. All the cell lines were irradiated by Carbon-SIS with LET of 100 keV/μm. However, 79HF6 cells and LAN-1 cells were also irradiated by Carbon-UNILAC with LET of 168 keV/μm and Nickel ions with LET of 174 keV/μm, respectively. The effect of radiation on the survival and proliferation of cells was addressed by standard clonogenic assays. In order to analyze cell karyotype standard Giemsa staining, multicolor fluorescence in situ hybridization (mFISH) and multicolor banding (mBAND) techniques were applied. RESULTS: Relative biological effectiveness values of heavy ion beams relative to X-rays at the D(10) values were found between 2.3 and 2.6 with Carbon-SIS and Nickel for LAN-1 and between 2.5 and 3.4 with Carbon-SIS and Carbon-UNILAC for 79HF6 cells. Chemorefractory LAN-1(RETO) cells were found more radioresistant than untreated LAN-1(WT) cells. 79HF6(RETO) glioblastoma cells were found more radiosensitive than cytostatic sensitive cells 79HF6(WT). Sphere formation assay showed that LAN-1(RETO) cells were able to form spheres in serum-free culture, whereas 79HF6 cells could not. Most of 79HF6(WT) cells revealed a number of 71–90 chromosomes, whereas 79HF6(RETO) revealed a number of 52–83 chromosomes. The majority of LAN-1(WT) cells revealed a number of 40–44 chromosomes. mFISH analysis showed some stable aberrations, especially on chromosome 10 as judged by the impossibility to label this region with specific probes. This was corroborated using mBAND analysis. CONCLUSION: Heavy ion irradiation was more effective than X-ray in both cytostatic naive cancer and chemoresistant cell lines. LAN-1(RETO) chemoresistant neuroblastoma cells were found to be more radioresistant than the cytostatic naive cells (LAN-1(WT)), whereas this effect was not found in 79HF6 cells