Biological effects caused by ionizing radiation have been investigated mainly using photons due to restrictions on available radiation sources. While HIMAC is the first synchrotron in the world specifically constructed for medical use, NIRS accepted and promoted basic sciences proposed by domestic and international researchers. Research at HIMAC produced many fruitful outcomes in high-LET radiation biology. We here review these outcomes and introduce a new development in the biology field using heavy-ion beams.

Hydroxyl radical (·OH) generation, hydrogen peroxide (H₂O₂) generation, and the total amount of oxidation reactions caused by X-ray or carbon-ion beam irradiation to aqueous samples were measured by electron paramagnetic resonance-based methods. The ·OH generation was expected to be localized on the track/range of the carbon-ion beam/X-ray, and millimolar- and molar-levels of ·OH generation were expected. The millimolar-level ·OH generation, H₂O₂ generation, and total oxidation reaction were suppressed with increasing linear energy transfer (LET). The generation of reactive oxygen species (ROS) was not uniform at the molecular level and was LET dependent. It can be expected that differences in ROS generation and the molecular distribution could make a difference in the quality of radiation therapy.

In this review, recent findings are introduced in terms of particle irradiation-induced DNA damage and repair, particularly DNA double-strand break repair, by HIMAC. Based on the studies using HIMAC, the structure of complex DNA lesion as well as clustered DNA double-strand breaks after high LET particle irradiation hav been identified. In addition, the molecular mechanisms underlying DNA repair pathway choice after particle ion irradiation has been uncovered. The comprehensive understanding of molecular mechanism regarding DNA damage and its repair proposes potential novel approaches to augment the efficacy of particle radiotherapy. In this review, recent significant findings obtained by using HIMAC are introduced by focusing on DNA damage and repair.

We introduce the results about the relative biological effectiveness (RBE) using HIMAC. Carbon-ion therapy is rated higher concerning the quality of life (QOL) than photon therapy because it has a strong cancer control ability and is considered to be a low-invasive method. It is important to evaluate the dose and to know the relations of linear energy transfer (LET) and RBE for understanding a useful effect of carbon-ion therapy. In this review, we summarize the current status and the meaning of the RBE concept in carbon-ion therapy and highlight outstanding issues.

High LET radiation is highly expected to control hypoxic fraction in tumor tissue that shows radiation resistance to low LET radiation, because oxygen effect decreases with increasing LET. Due to the availability of various ions and LETs, HIMAC has produced many outcomes from basic to clinical studies. In the basic studies, the mechanism of decreasing oxygen effect with increasing LET was experimentally examined based on the previously proposed “oxygen in the track” model. In addition, in vitro cellular and in vivo transplanted tumor studies demonstrated the LET dependent feature of DNA damage produced under hypoxic condition. For the effort to connect basic studies to clinical trials, measurement of LET dependence of OER (Oxygen Enhancement Ratio) was extended to various oxygen concentrations to mimic oxygen environment in tumors. Finally clinical research using carbon ions for cervical cancer patients demonstrated the effective control of hypoxic fraction.

Radioadaptive response, genetic instability, bystander response and low dose hyper-radiosensitivity are known as specific cellular responses against low dose radiation exposure. However, their induction mechanisms are fully unknown. In the present section, the induction mechanisms for radiation-induced bystander response and radioadaptive response, which were elucidated by us using heavy particle ion beams in HIMAC, are reviewed.

In carbon-ion therapy, superiority of the physical dose distribution leads to a reduction in the number of fractions or may even allow hypofractionation. Several clinical trials are currently underway to evaluate the clinical effect of fractionated carbon-ion therapy. However, the biological effects of fractionation in carbon-ion beams hasn’t been investigated in detail. In this review, we will summarize the meaning of the fractionation and introduce mainly about previous study and our knowledge in the biological effects of fractionation using HIMAC.

One in two people has suffered from cancer in Japan. Cancer has a specific property, called metastasis. Metastasis and recurrence are extremely important factors that determine the prognosis of various cancer treatments. Recent advances in the field of radiotherapy have considerably improved the treatment outcome of various types of cancer based on the benefits of advances in oncology, physics, engineering, biology etc. Although the number of cancer patients receiving radiotherapy is increasing, knowledge about radiation effects on metastasis is not sufficient and radiotherapy targeting metastasis is extremely undeveloped. Experiments using various particle ion species and linear energy transfer are possible with HIMAC of NIRS. By using this facility, it is possible to examine the influence of not only “quantity” but also “quality” of radiation, and to obtain useful data that can contribute to radiation cancer metastasis research.

Heavy ion radiotherapy is expected to reduce the risk of second cancer by decreasing exposure of normal tissues to radiation. Emerging studies have attempted to predict the risk of second cancer after carbon ion radiotherapy based on dose assessment, the epidemiologically-identified risk of photon radiation, and assumptions about the relative biological effectiveness (RBE) of carbon ions. Nevertheless, large uncertainty remains in the choice of RBE of carbon ions in inducing cancer. The present article summarizes carcinogenesis experiments performed in animals using HIMAC. These animal experiments have yielded RBE values for selected tissues, beam types, and age at the time of irradiation. The results indicate potentially variable RBE which depends on tissues, ages, and dose levels. A few additional studies have attempted to identify molecular alterations in tumors induced by carbon ions. Thus, more comprehensive animal carcinogenesis studies are needed.

HIMAC, a therapeutic accelerator, has also been used for basic research, including various types of biological studies. Some of these studies, have attempted to expand the applications of heavy particle beams (ion beams) to other than cancer treatment; research on disease treatment other than cancer and breeding research can be cited. These projects, such as ion-beam breeding and non-invasive disease treatment other than cancer aim to enrich our lives by newly utilizing ion beams in new ways. In this review, we will introduce these studies and achievements that have been carried out at HIMAC, and discuss benefits that are expected to return to society owing to the results of these projects.