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We studied the relation between initial DNA double-strand breaks (DNA-DSB) and the rejoining kinetics of the strand breaks, as well as the OER (oxygen enhancement ratio) after low- and high-LET (linear energy transfer) radiations. CHO cells were exposed to 200 kVp X-rays or 80 keV/microm carbon ions under oxic and hypoxic conditions. DNA-DSB in the cells were analyzed by a static-field gel electrophoresis (SFGE). The kinetics of the rejoining could be described by a sum of fast and slow components. The initial released DNA after X-ray irradiation was higher for cells irradiated under an oxic condition than that under a hypoxic condition. The OER of DNA-DSB after X-ray irradiation was 5.7. This value decreased rapidly to be 3.4 with the fast component by 15 minutes. On the other hand, the OER of DNA-DSB after carbon ion irradiation was 2.2, and this value was not changed by rejoining incubation. The OER values for cell killing were 2.8 and 1.8 after X-ray and carbon ion irradiations, respectively. These values matched to the OER for DNA-DSB with complete rejoining. We conclude that the rejoining of DNA-DSB is an important factor in the mechanism of the oxygen effect.

The biological effectiveness of carbon ions relative to γ rays (RBE) was compared between the tumor growth delay and an early skin reaction of syngeneic mice. The RBE was larger for a tumor than skin when irradiated with large doses of high-LET (linear energy transfer) carbon ions. The intra-track damage (a term of a linear quadratic model) of a tumor and skin increased equally with an increase of the LET, while the inter-track damage (β term) of skin alone increased with the LET. These data provide evidence that high-LET radiotherapy could achieve therapeutic gain by minimizing the difference in response to fractionated irradiation between the tumor and normal tissue.

It is well established that the RBE (relative biological effectiveness) for cell killing depends on LET (linear energy transfer), and that a maximum RBE is observed at ~150 keV/mm. However, the therapeutic gain depends on the ratio of the RBEs for the effects on the cancer cell population and the effects on normal tissues. The RBE of a given radiation quality depends on LET but also on dose, biological system and effect, and irradiation conditions. There is no data available to answer the question: which LET is suitable to improve the biological therapeutic gain of carbon ions? Here, we selected 3 different LET values of 290 MeV/u carbon ions, and compared the relative biological effectiveness between tumor-growth retardation and skin damage using a murine transplantable tumor. Larger RBE values for tumors after than the skin type were obtained when carbon-ions of intermediate LET were daily delivered for 2 through 5 fractions. The biological therapeutic gain would be high for the carbon-ion SOBP if the number of fractions were correctly selected in clinical trials.

56th Annual Meeting of Radiation Research Society

Background: To investigate the differences between two rat yolk sac tumor cell lines with different radiosensitivities in sensitivity to high-LET heavy ion beam and in sensitizing effect of etoposide (DNA topoisomerase II inhibitor) in combination with heavy ion beam. Material and methods: NMT-1 (wild-type p53 cell) is a parent radiosensitive cell line and NMT-1R (mutant-type p53 cell) is a variant radioresistant cell line. Heavy ion (carbon ion) was accelerated to 290 MeV/u by a heavy-ion medical accerelator in Chiba at National Institute of Radiological Sciences. The dose average LET value in the samples was 80 keV/um. The effects of carbon ion irradiation were assessed by clonogenic assay. The concentration of etoposide required to reduce colony formation by 50% at 1-hour treatment (IC50 of etoposide) was selected for heavy ion irradiation pretreatment for each cell line. The RBE (relative biological effect) of the carbon ion beams to X-rays was calculated for D10 (10% survival dose). Results: There was no significant difference between NMT-1 cells and NMT-1R cells in sensitivity to high-LET heavy ion irradiation (LET;80keV/um) and no shoulder in dose-response curve. The RBE was 1.41 for NMT-1 and 2.16 for NMT-1R, respectively. The RBE of carbon beam was larger in mutant-type p53 cells than in wild-type p53 cells. Etoposide showed a supra-additive effect in combination with carbon beam irradiation in NMT-1R cells. Etoposide potentiation in NMT-1R cells was manifested by the decrease in the slope of the radiation dose-response curve. However, there was no enhancement effect in radiosensitive NMT-1 cells. Conclusions: Our findings suggested that high-LET radiotherapy is expected to be effective for patients carrying radioresistant tumors and mutated p53 tumor cells. Etoposide might be effective for radioresistant tumors in combination with heavy ion beam irradiation., ECCO 13

The Sixth China-Japan Joint Seminar on Radiopharmaceutical Chemistry

放射線治療後において，MRIやCTでは治療効果を判定するには数週間を要するため，治療後早期の効果判定は腫瘍増殖能や照射計画を推測する上で重要であると考えられる．そこで今回我々はThymidineおよびFDGを用いたダブルトレーサ法により，炭素線照射後の腫瘍体積の変化が認められない早期(12時間後)と再増殖時期（14日後）におけるDNA合成能と糖代謝について検討を行った． 【方法】C3H雄性マウスの下肢にNFSa腫瘍を移植し，腫瘍直径が7.5mmのマウスに線量およびLET(14keV/μm，74keV/μm)の異る炭素線(6cm-SOBP)を照射して腫瘍体積を経日的に計測した．またDNA合成能と糖代謝を計測するため，照射12時間後と14日後に炭素線を照射したマウスに，18F-DGおよび14C-Thymidineを尾静脈投与した．投与30分後に屠殺して速やかに下肢腫瘍と筋肉および血液(Plasma)を採取し，液体シンチレーションカウンターで計測した． 【結果・考察】腫瘍体積は照射後2日まで，照射群（3-60Gy）は非照射群と比べ変化は認められなかった．糖代謝は照射12時間後では，照射群において軽度の減少がみられるもののLETおよび線量依存性(22-40Gy)は認められなかった．また腫瘍再増殖がみられる照射14日後においても変化は認められなかった．一方で，14C-Thymidine取込能は照射12時間後に，線量およびLETに依存した有意な取込能の減少が認められ，照射12時間後の腫瘍取込能と照射14日後の腫瘍体積との間に高い相関性が認められた．さらに照射14日後においては，腫瘍増殖速度に応じた取込能の増大が認められた．以上の結果から，14C-Thymidineは照射後早期において放射線治療効果を判定すると共に，再発する腫瘍の増殖速度を推定出来ることが示唆された．, 第48回日本放射線影響学会

High LET radiation minimizes any difference in the radiosensitivity of different types of cells to which photon irradiation produces large variation. It is anticipated that side effects of high LET particle radiotherapy would not bring a biological therapeutic gain. The purpose of this paper is to answer a question whether high LET radiation could discriminate tumor and normal tissues so that biological advantage could be achieved. We here selected and measured the growth delay of an experimental tumor and the skin reaction in C3H mice, as a model for biological gain. The tumor was a syngeneic NFSa fibrosarcoma, and were transplanted intramuscularly into the right hind legs of male mice 7 days before the first irradiation. Hairs on the right hind leg of female mice were removed by applying a depilatory agent 7 to 8 days before the first irradiation. Carbon-12 ions were accelerated by the HIMAC synchrotron up to 290 MeV/u. Cs-137 gamma-rays were used as a reference beam for determining the RBE. Daily fractionation was given with equal daily doses using an interfractional interval of 24 hours. Several graded doses were used to determine an isoeffect dose, and animals assigned to a given dose group received equal daily doses. The tumor growth (TG) time obtained for all animals were averaged per each dose group. Irradiated legs were observed for skin reaction scoring every other day up to 5 weeks. The skin scores in an individual mouse were averaged, and was used for obtaining dose-response. Carbon ions of LET 42 and 77 keV/micro.m, but not 14 or 20 keV/ micro.m, showed larger RBE values in retarding tumor growth than causing skin reaction after daily-fractionated irradiation. Using Fe-plot, we analyzed the isoeffect dose to evaluate dependence of intra-track damages (alpha term) and of inter-track damages (beta terms) on LET. The alpha term of tumor growth delay and skin reaction equally increased with an increase in LET, and no difference was observed between the two tissues. Beta term was, however, different between the two tissues such that the beta term of skin reaction apparently increased with LET while that of tumor growth delay was independent of LET. It is clear that beta term is a determinant of tissue specific response to high LET radiation, while alpha term solely depends on LET. It is implied that high-LET radiotherapy could achieve a large therapeutic gain when a large dose per fraction is used., 9th workshop on Heavy Charged Particles in Biology and Medicine and 3rd ENLIGHT co-ordination meeting

INTRODUCTION HIMAC (Heavy-ion Medical Accelerator in Chiba) has constructed in 1993, and clinical trials has started in 1994 together with academic research activities, including physics, engineering, and biology. Pre-clinical radiobiological studies have performed to estimate clinical RBE for hadron beams. Following the HIMAC, several hadron therapy facilities (HIBMC, Hyogo; NCCHE, Kashiwa; WERC, Tsuruga; PMRC, Tsukuba; SCC, Shizuoka) have started the therapy in Japan. We have evaluated the RBE of each hadron beams for all the facilities with the same biological system and technical staffs as well as at HIMAC. METHODS Human salivary gland tumor cells (HSG) were used for the studies. All experiments were performed with single-dose exposures for both proton beams and linac X-rays at each facilities. All 60 mm SOBP beams were generated from 180-190 MeV proton beam, and the energy of high-energy linac X-rays were 4-6 MeV, but it depends on the facilities. Samples were placed at the plateau position or the entrance, middle, or proximal positions of SOBP beam or at the 50 mm depth position of the linac beam. The D10 values from survival curves by the colony formation assay were obtained. The RBE values of proton beams were calculated to X-ray data. RESULTS The average RBE at the middle of SOBP beam from all facilities was 1.030+/-0.017 (mean +/- SD). Flatness of the RBE in the SOBP were slightly disposed to increase with the depth. The values were slightly lower at the entrance, and little bit higher at the distal than that at the middle position. DISCUSSION X-ray data showed very good agreement and the deviations were less than 2 % among the facilities. The RBE values also showed good agreement among the facilities with 2 % or less standard deviation. Some difficulties were found in the irradiation systems, i.e. the dose determination and/or geometrical sample setting methods are different among the facilities. This may makes difficult exact comparative judgments of the radiobiological data. During the radiobiological experiments process, several problems were found and have solved. In this point of view, preclinical experiments were important as a simulation of patient treatments. CONCLUSION The RBE values for all proton therapy facilities in Japan were similar (1.02) with small deviation. The depth-dose distribution of all the SOBP beams has designed very well, and showed good uniformities of biological dose at all facilities. Physical dosimetry system should be unify for all the facilities to compare the results., WC2003

The purpose of this paper is to report that gut crypt cells become radioresistant after single or fractionated irradiation with intermediate LET carbon ions. C3H female mice received whole body irradiation with 20 keV/mm carbon ions, and served the jejunum for crypt survival assay 3.5 days after irradiation. Dose-crypt survival relationship showed that the D0 value increased from 1.06 Gy to 1.94 Gy when the first dose of 9.0 Gy was followed by single graded doses of carbon ions with an interval time of 4 hr. The Increased D0 gradually decreased with a half decay time of 50 hr, and returned to 1.08 Gy, a similar value of single irradiation. When mice received 1 Gy carbon ions for 9 fractions with an interval time of 4 hr each, the D0 value of crypt cells surviving the preceding total dose of 9 Gy also increased to 1.89 Gy. The D0 increase was less prominent when the size of first or preceding dose was small. It is concluded that charged particles with intermediate LET produce a unique biological response, and would be beneficial for radiotherapy of visceral tumors., ICRR

HCPBM and ENLIGHT-2002

HCPBM and ENLIGHT-2002

HCPBM and ENLIGHT-2002

Europian Radiation Research 2001

13th Symposium on Microdosimetry