Experimental verification of therapeutic doses for the superficially-placed tumor radiotherapy with heavy ions at HIRFL

Up to now, clinical trials of heavy-ion radiotherapy for superficially placed tumors have been carried out for six times and over 60 selected patients have been treated with 80—100 MeV/u carbon ions supplied by the Heavy Ion Research Facility in Lanzhou (HIRFL) at the Institute of Modern Physics, Chinese Academy of Sciences since November, 2006. A passive irradiation system and a dose optimization method for radiotherapy with carbon-ion beams have been developed. Experimental verification of longitudinally ...

Studies on advantages of heavy ions in radiotherapy compared with gamma-rays

Hepatoma and melanoma cells were exposed to C-12(6+) beams generated by HIRFL facility and gamma-rays and the cell response was studied by colony assays as well as the analysis of RBE of carbon ions was evolved. The survival curves of cells irradiated by heavy ions were different from those of cells irradiated by gamma-rays. And two kinds of cell showed the obvious discrepancy in response to the photon and ion irradiation. The results showed that heavy ions have special physical properties and mighty potency to kill cell in both single and fractional irradiation meanwhile it can kill tumor cells with high radioresistance more efficiently. When involved in clinical therapy, heavy ions will enhance the therapy efficiency and decrease the suffering of patients because it can impair the repair for sublethal damage of cells which can lead to fewer irradiation fractions.

Conformal irradiation to moving targets in heavy ion radiotherapy with raster-scanning beam delivery system: (II) feasibility experiments

Within the framework of the pilot heavy-ion therapy facility at GSI equipped with an active beam delivery system of advanced raster scanning technique, a feasibility study on actively conformal heavy-ion irradiation to moving tumors has been experimentally conducted. Laterally, real-time corrections to the beam scanning parameters by the raster scanner, leading to an active beam tracing, compensate for the lateral motion of a target volume. Longitudinally, a mechanically driven wedge energy degrader (called depth scanner) is applied to adjust the beam energy so as to locate the high-dose Bragg peak of heavy ion beam to the slice under treatment for the moving target volume. It has been experimentally shown that compensations for lateral target motion by the raster scanner and longitudinal target shift by the depth scanner are feasible.

重离子束治疗皮肤恶性肿瘤的初步临床结果；Clinical trial of carbon ion radiotherapy for malignant neoplasm of skin

目的:评价重离子束对皮肤恶性肿瘤放射治疗的近期疗效和毒副反应。方法:29例皮肤恶性肿瘤患者分6批接受重离子束放射治疗,其中恶性黑色素瘤13例,皮肤鳞癌及Bowen’s病各6例,基底细胞癌2例,其他皮肤恶性肿瘤2例。照射总剂量(50～70)GyE/(6～12)d,单次剂量5.5～11.67GyE,1f/d,连续治疗。采用RTOG标准和WHO近期疗效标准分别评价毒副反应和近期疗效。结果:截止2009-05,中位随访时间为13.5个月(1～25个月),随访率为100%。29例患者中完全缓解(CR)24例(82.8%),部分缓解(PR)5例(17.2%),有效率(RR)为100%,中位生存时间为22.8个月(95%CI:20.6～24.9)。皮肤反应0度11例(37.9%),Ⅰ度9例(31.0%),Ⅱ度6例(20.7%),Ⅲ度2例(6.9%),Ⅳ度1例(3.4%);血液毒副反应治疗前后无明显改变。结论:重离子束(12C6+)放射治疗皮肤恶性肿瘤近期疗效好,并发症轻,远期疗效、晚期副反应等尚需进一步长期全面的观察和更多的研究提供依据。

Adenovirus-mediated wild-type P53 Transfer radiosensitizes H1299 cells to subclinical-dose carbon-ion irradiation through the restoration of p53 function

To determine whether adenovirus-mediated wild-type p53 transfer after radiotherapy could radiosensitize non-small-cell lung cancer (NSCLC) cells to subclinical-dose carbon-ion beam (C-beam), H1299 cells were exposed to a C-beam or -ray and then infected with 5 MOI of AdCMV-p53 or GFP (C-beam or -ray with p53 or GFP).Cell cycle was detected by flow cytometric analysis. The apoptosis was examined by a fluorescent microscope with DAPI staining. DNA fragmentation was monitored by the TUNEL assay. P53 mRNA was detected by reverse-transcriptase polymerase chain reaction. The expression of p53, MDM2, and p21 was monitored by Western blot. Survival fractions were determined by colony-forming assay. The percentages of G1-phase cells in C-beam with p53 increased by 8.2%–16.0%, 5.2%–7.0%, and 5.8%–18.9%, respectively, compared with C-beam only, -ray with p53, or p53 only. The accumulation of G2-phase cells in C-beam with p53 increased by 5.7%–8.9% and 8.8%–14.8%, compared with those in -ray with p53 or p53 only, respectively. The percentage of apoptosis for C-beam with p53 increased by 7.4%–19.1%, 5.8%–11.7%, and 5.2%–19.2%, respectively, compared with C-beam only, -ray with p53, or p53 only. The level of p53 mRNA in C-beam with p53 was significantly higher than that in p53 only. The expression level of p53 and p21 in C-beam with p53 was significantly higher than that in both C-beam with GFP and p53 only. The survival fractions for C-beam with p53 were significantly less than those for the other groups (p 0.05). The data suggested that AdCMV-p53 transfer could more efficiently radiosensitize H1299 cells to subclinical-dose C-beam irradiation through the restoration of p53 function.

Radiosensitivity of hepatoma cell lines and human normal liver cell lines exposed in vitro to carbon ions and argon ions at the HIRFL

Human hepatoma (SMMC-7721) and normal liver (L02) cells were irradiated with c-rays, 12C6+ and 36Ar18+ ion beams at the Heavy Ion Research Facility in Lanzhou (HIRFL). By using the Calyculin-A induced premature chromosome condensation technique, chromatid-type breaks and isochromatid-type breaks were scored separately. Tumor cells irradiated with heavy ions produced a majority of isochromatid break, while chromatid breaks were dominant when cells were exposed to c-rays. The relative biological effectiveness (RBE) for irradiation-induced chromatid breaks were 3.6 for L02 and 3.5 for SMMC-7721 cell lines at the LET peak of 96 keVlm 1 12C6+ ions, and 2.9 for both of the two cell lines of 512 keVlm 1 36Ar18+ ions. It suggested that the RBE of isochromatid-type breaks was pretty high when high-LET radiations were induced. Thus we concluded that the high production of isochromatid-type breaks, induced by the densely ionizing track structure, could be regarded as a signature of high-LET radiation exposure.

NADPH oxidase-mediated generation of reactive oxygen species: A new mechanism for X-ray-induced HeLa cell death

Oxidative damage is an important mechanism in X-ray-induced cell death. Radiolysis of water molecules is a source of reactive oxygen species (ROS) that contribute to X-ray-induced cell death. In this study, we showed by ROS detection and a cell survival assay that NADPH oxidase has a very important role in X-ray-induced cell death. Under X-ray irradiation, the upregulation of the expression of NADPH oxidase membrane Subunit gp91(phox) was dose-dependent. Meanwhile, the cytoplasmic subunit p47(phox) was translocated to the cell membrane and localized with p22(phox) and gp91(phox) to form reactive NADPH oxidase. Our data Suggest, for the first time, that NADPH oxidase-mediated generation of ROS is an important contributor to X-ray-induced cell death. This suggests a new target for combined gene transfer and radiotherapy.

The influence of fractionation on cell survival and premature differentiation after carbon ion irradiation

Carbon ion radiotherapy/Fractionated irradiation/R-BE/Premature terminal differentiation. To investigate the influence of fractionation on cell survival and radiation induced premature differentiation as markers for early and late effects after X-rays and carbon irradiation. Normal human fibroblasts NHDF, AG1522B and WI-38 were irradiated With 250 kV X-rays, or 266 MeV/u, 195 MeV/u and I I MeV/u carbon ions. Cytotoxicity was measured by a clonogenic survival assay or by determination of the differentiation pattern. Experiments with high-energy carbon ions show that fractionation induced repair effects are similar to photon irradiation. The RBE10 values for clonogenic survival are 1.3 and 1.6 for irradiation in one or two fractions for NHDF cells and around 1.2 for AG1522B cells regardless of the fractionation scheme. The RBE for a doubling of post mitotic fibroblasts (PMF) in the population is I for both single and two fractionated irradiation of NHDF cells. Using I I MeV/u carbon ions, no repair effect can be seen in WI-38 cells. The RBE10 for clonogenic survival is 3.2 for single irradiation and 4.9 for two fractionated irradiations. The RBE for a doubling of PMF is 3.1 and 5.0 for single and two fractionated irradiations, respectively. For both cell lines the effects of high-energy carbon ions representing the irradiation of the skin and the normal tissue in the entrance channel are similar to the effects of X-rays. The fractionation effects are maintained. For the lower energy, which is representative for the irradiation of the tumor region. RBE is enhanced for clonogenic survival as well as for premature terminal differentiation. Fractionation effects are not detectable. Consequently, the therapeutic ratio is significantly enhanced by fractionated irradiation with carbon ions.

Rotating wheel filter design and optimization for a uniform depth dose distribution in heavy ion therapy

Treatment planning of heavy-ion radiotherapy involves predictive calculation of not only the physical dose but also the biological dose in a patient body. The goal in designing beam-modulating devices for heavy ion therapy is to achieve uniform biological effects across the spread-out Bragg peak (SOBP). To achieve this, a mathematical model of Bragg peak movement is presented. The parameters of this model have been resolved with Monte Carlo method. And a rotating wheel filter is designed basing on the velocity of the Bragg peak movement.

Advance in in-beam PET

Tumor radiotherapy was a promising modality and over 100 years. Beams of heavy-charged particles show high RBE advantages and become the optimum tool for tumors therapy. Newly, along with the development of accelerators, scintillators, micro-electronics and computers, the heavy ion tumor therapy has been recognized more and developed.

A correlation between radiation sensitivity and initial chromatid breaks in cancer cell lines revealed by Calyculin A-induced premature condensation

Three human malignancy cell lines were irradiated with Co-60 gamma-rays. Initial chromatid breaks were measured by using the chemically induced premature chromosome condensation technique. Survival curves of cells exposed to gamma rays was linear-quadratic while the efficiency of Calyculin A in inducing PCC of G(2) PCC was about five times more than G(1) PCC. A dose-dependent increase in radiation-induced chromatid/isochromatid breaks was observed in G(1) and G(2) phase PCC and a nearly positive linear correlation was found between cell survival and chromatin breaks. This study implies that low LET radiation-induced chromatid/isochromatid breaks can potentially be used to predict the radiosensitivity of tumor cells either in in vitro experimentation or in in vivo clinical radiotherapy.

Correlation between initial chromatid damage and survival of various cell lines exposed to heavy charged particles

The biophysical characteristics of heavy ions make them a rational source of radiation for use in radiotherapy of malignant tumours. Prior to radiotherapy treatment, a therapeutic regimen must be precisely defined, and during this stage information on individual patient radiosensitivity would be of very great medical value. There are various methods to predict radiosensitivity, but some shortfalls are difficult to avoid. The present study investigated the induction of chromatid breaks in five different cell lines, including one normal liver cell line (L02), exposed to carbon ions accelerated by the heavy ion research facility in Lanzhou (HIRFL), using chemically induced premature chromosome condensation (PCC). Previous studies have reported the number of chromatid breaks to be linearly related to the radiation dose, but the relationship between cell survival and chromatid breaks is not clear. The major result of the present study is that cellular radiosensitivity, as measured by D-0, is linearly correlated with the frequency of chromatid breaks per Gy in these five cell lines. We propose that PCC may be applied to predict radiosensitivity of tumour cells exposed to heavy ions.

Germ cell loss induced by C-12(6+) ion irradiation in young female mice

The ovaries of Kun-Ming strain mice (3 weeks) were irradiated with different doses of C-12(6+) ion in the Bragg peak or the plateau region. At 10th day after irradiation, ovarian and uterine weights were measured: normal and atretic (identified with the oocyte to be degenerating or absent) primordial, primary and preantral follicles were identified in the largest cross-section of each ovary. Percentage (%) of normal follicles of each developmental stage of oogenesis was calculated. The data showed that compared to controls, there was a dose-related decrease in percentage of normal follicles in each developmental stage. And the weights of ovary and uterus were also reduced with doses of irradiation. Moreover, these effects were much more significant in the Bragg peak region and the region close to the Bragg peak than in the beam's entrance (the plateau region). Radiosensitivity varied in different follicle maturation stages. Primordial follicles, which are thought to be extremely sensitive to ionizing irradiation, were reduced by 86.6%, while primary and preantral follicles reduced only by 72.5% and 61.8% respectively, by exposure with 6 Gy of C-12(6+) ion in the Bragg peak region and the region close to the Bragg peak. The data suggested that due to their optimal depth-dose distribution in the Bragg peak region, heavy ions are ones of the best particles for radiotherapy of tumors located next of vital organs or/and surrounded by normal tissues, especially radiosensitive tissues such as gonads.

Effect of p53 on lung carcinoma cells irradiated by carbon ions or X-rays

The study is to investigate the feasibility and advantages of heavy ion beams on radiotherapy. The cellular cycle and apoptosis, cell reproductive death and p53 expression evaluated with flow cytometry, clonogenic survival assays and Western blot analysis were examined in lung carcinoma cells after exposure to 89.63 MeV/u carbon ion and 6 MV X-ray irradiations, respectively. The results showed that the number colonyforming assay of A549 was higher than that of H1299 cells in two radiation groups; A549 cellular cycle was arrested in G(2)/M in 12 It and the percentage of apoptosis ascended at each time point of carbon ion radiation with doses, the expression of p53 upregulated with doses exposed to X-ray or carbon ion. The cell number in G(2)/M of H1299 and apoptosis were increasing at all time points with doses in C-12(6+) ion irradiation group. The results suggested that the effects of carbon ions or X rays irradiation on lung carcinoma cells were different, C-12(6+) ion irradiation could have more effect on upregulating the expression of p53 than X-ray, and the upregulated expression of p53 might produce the cellular cycle G(2)/M arrested, apoptosis increasing; and p53 gene might affect the lung cancer cells radiosensitivity.