Proton-Cluster-Beam Lethality and Mutagenicity in Bacillus subtilis Spores

The unique energy transfer characteristics of swift cluster ions have attracted the attention of many researchers working on the analysis or processing of material surfaces, but the effects on living organisms remain unclear. We irradiated B. subtilis spores with monomer and cluster proton beams and examined their lethality; the 2 MeV H2+ shows a clearly lower lethality than 340 keV H+, even though both have a comparable linear energy transfer. The 2 MeV H2+ dissociates into a pair of 1 MeV H+ by losing the bonding electrons at the target surface. The estimated internuclear distance and the radial dose distribution suggest that the spread of deposited total energy over two areas separated by just several nanometers greatly diminishes beam lethality and that the energy density in the very center of the trajectory, possibly within a 1 nm radius, has a great impact on lethality. We also performed a whole genome resequencing of the surviving colonies to compare the molecular nature of mutations but failed to find a clear difference in overall characteristics. Our results suggest that cluster beams may be a useful tool for understanding biological effects of high linear energy transfer radiation.

High LET-Like Radiation Tracks at the Distal Side of Accelerated Proton Bragg Peak

Proton therapy is a type of hadron radiotherapy used for treating solid tumors. Unlike heavy charged elements, proton radiation is considered to be low LET (Linear Energy Transfer) radiation, like X-rays. However, the clinical SOBP (Spread Out Bragg Peak) proton radiation is considered to be higher in relative biological effectiveness (RBE) than both X-ray and their own entrance region. The RBE is estimated to be 1.1–1.2, which can be attributed to the higher LET at the SOBP region than at the entrance region. In order to clarify the nature of higher LET near the Bragg peak of proton radiation and its potential cytotoxic effects, we utilized a horizontal irradiation system with CHO cells. Additionally, we examined DNA repair mutants, analyzed cytotoxicity with colony formation, and assessed DNA damage and its repair with γ-H2AX foci assay in a high-resolution microscopic scale analysis along with the Bragg peak. Besides confirming that the most cytotoxic effects occurred at the Bragg peak, extended cytotoxicity was observed a few millimeters after the Bragg peak. γ-H2AX foci numbers reached a maximum at the Bragg peak and reduced dramatically after the Bragg peak. However, in the post-Bragg peak region, particle track-like structures were sporadically observed. This region contains foci that are more difficult to repair. The peak and post-Bragg peak regions contain rare high LET-like radiation tracks and can cause cellular lethality. This may have caused unwanted side effects and complexities of outputs for the proton therapy treatment.

The Role of Particle Therapy in Adenoid Cystic Carcinoma and Mucosal Melanoma of the Head and Neck

Particle irradiation is suitable for resistant histologies owing to a combination of improved dose delivery with potential radiobiologic advantages in high linear energy transfer radiation. Within the head and neck, adenoid cystic carcinoma and mucosal melanoma are two such histologies, being radioresistant and lying closely proximal to critical structures. Here, we review the use of particle irradiation for adenoid cystic carcinoma and mucosal melanoma of the head and neck.

Hyperthermia: The Optimal Treatment to Overcome Radiation Resistant Hypoxia

Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39–45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination.