The sharp high dose Bragg peak of a carbon-ion beam helps it to deliver the highest dosage to the malignant cells while leaving the normal cells relatively unharmed. However, the precise range in which it distributes dosages that significantly induce cell death or genotoxicity surrounding its Bragg peak remains unclear. To evaluate biological effects of carbon-ion radiation through entrance to post Bragg peak in a single biological system, CHO and xrs5 cells were cultured in T-175 cell culture flasks and irradiated with 290 MeV/n monoenergetic carbon-ions with initial dosages upon entrance to the flask of 1, 2, or 3 Gy for cell survival assays or 1 Gy for cytokinesis block micronuclei assays. Under all initial dosages, the biological Bragg peak and the highest micronuclei formation was observed at the depth of 14.5 cm. Moreover, as the initial dosage increased the range displaying a significant decrease in survival fraction increased as well ( P < 0 . 0001 ). Intriguingly from 1 Gy to 3 Gy, we observed a significant increase in reappearance of colony formation depth ( P < 0 . 05 ), possibly indicating the nuclear fragmentation lethality potential of the carbon-ion. By means of our single system approach, we can achieve a more comprehensive understanding of biological effects surrounding of carbon-ions Bragg peak.
DNA double-strand breaks (DSBs) are the main factor behind carbon-ion radiation therapy (CIRT)-induced cell death. Nuclear interactions along the beam path between the primary carbon ions and targets result in nuclear fragmentation of carbon ions and recoiled particles. These secondary particles travel further distances past the Bragg peak to the tail region, leading to unwanted biological effects that may result in cytotoxicity in critical organs and secondary induced tumors following CIRT. Here, we confirmed that the density of the DSB distributions increases as the cell survival decreases at the Bragg peak and demonstrated that by visualizing DSBs, the various LET fragmentation ions and recoiled particles produced differences in their biological effects in the post-Bragg peak tail regions. This suggests that the density of the DSBs within the high-LET track structures, rather than only their presence, is important for inducing cell death. These results are essential for CIRT treatment planning to limit the amount of healthy cell damage and reducing both the late effect and the secondary tumor-associated risk.
DMSO, glycerol, and ascorbic acid (AA) are used in pharmaceuticals and known to display radioprotective effects. The present study investigates radioprotective properties of novel glyceryl glucoside, ascorbic acid 2-glucoside, glyceryl ascorbate, and palmitoyl ascorbic acid 2-glucoside (PA). Gamma-rays or high-LET carbon-ions were irradiated in the presence of tested chemicals. Lambda DNA damage, cell survival, and micronuclei formation of CHO cells were analyzed to evaluate radioprotective properties. Radiation-induced Lambda DNA damage was reduced with chemical pre-treatment in a concentration-dependent manner. This confirmed tested chemicals were radical scavengers. For gamma-irradiation, enhanced cell survival and reduction of micronuclei formation were observed for all chemicals. For carbon-ion irradiation, DMSO, glycerol, and PA displayed radioprotection for cell survival. Based on cell survival curves, protection levels by PA were confirmed and comparable between gamma-rays and high-LET carbon-ions. Micronuclei formation was only decreased with AA and a high concentration of glycerol treatment, and not decreased with PA treatment. This suggests that mechanisms of protection against high-LET carbon-ions by PA can differ from normal radical scavenging effects that protect DNA from damage.
Quercetin has been demonstrated to produce DNA damage in the presence of metal ions. In the present study, 7 natural and 5 semi‑synthetic glycosylated flavonoids were utilized to investigate the cupric ion (Cu2+)‑dependent DNA damage in vitro. The reaction mixture, containing single‑stranded DNA, different concentrations of flavonoids and cupric ion in the buffer, was incubated at three different temperatures. DNA damage was then assessed by gel electrophoresis followed by densitometric analysis. The reaction mixture with quercetin at 4, 20 and 54˚C induced DNA damage in a concentration‑ and temperature‑dependent manner. Furthermore, only the reaction at 54˚C resulted in DNA damage in flavonoids with glucosyl substitution of the hydroxyl group at the 3‑position on the C ring in quercetin. By contrast, loss of the hydroxyl group at the 3‑position on the C ring, or at the 3'‑ or 4'‑position on the B ring of quercetin, did not portray DNA damage formation at the investigated experimental temperatures. In addition, the experimental results suggested that the hydroxyl group at the 3‑position on the C ring produced the strongest capability to induce DNA damage in the presence of cupric ions. Furthermore, hydroxyl groups at the 3'‑ or 4'‑position on the B ring were only able to induce DNA damage at higher temperatures, and were less efficient in comparison with the hydroxyl group at the 3‑position on the C ring. Cupric ion chelating capacity was also assessed with spectroscopic analysis, and quercetin presented the largest chelating capacity among the tested flavonoids. Hydroxyl radical formation was assessed with a luminol reaction, and quercetin presented faster consumption of luminol. These results suggest that the 3‑position hydroxyl group of the C ring is required to induce DNA damage at low temperatures. Furthermore, the results of the present study also indicated that the presence of cupric ions will decrease the activity of the glycosylated quercetins, in terms of their ability to induce DNA damage.
Phototherapy using narrowband ultraviolet-B (NB-UVB) has been shown to be more effective than conventional broadband UVB (BB-UVB) in treating a variety of skin diseases. To assess the difference in carcinogenic potential between NB-UVB and BB-UVB, we investigated the cytotoxicity via colony formation assay, genotoxicity via sister chromatid exchange (SCE) assay, mutagenicity via hypoxanthine phosphoribosyltransferase (HPRT) mutation assay, as well as cyclobutane pyrimidine dimer (CPD) formation and reactive oxygen species (ROS) generation in Chinese hamster ovary (CHO) and their NER mutant cells. The radiation dose required to reduce survival to 10% (D10 value) demonstrated BB-UVB was 10 times more cytotoxic than NB-UVB, and revealed that NB-UVB also induces DNA damage repaired by nucleotide excision repair. We also found that BB-UVB more efficiently induced SCEs and HPRT mutations per absorbed energy dosage (J/m2) than NB-UVB. However, SCE and HPRT mutation frequencies were observed to rise in noncytotoxic dosages of NB-UVB exposure. BB-UVB and NB-UVB both produced a significant increase in CPD formation and ROS formation (p < 0.05); however, higher dosages were required for NB-UVB. These results suggest that NB-UVB is less cytotoxic and genotoxic than BB-UVB, but can still produce genotoxic effects even at noncytotoxic doses.
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