Abstract
Radiation damage to normal tissues is one of the most serious concerns in radiation therapy, and the tolerance dose of the normal tissues limits the therapeutic dose to the patients. p53 is well known as a transcription factor closely associated with radiation-induced cell death. We recently demonstrated the protective effects of several p53 regulatory agents against low-LET X- or γ-ray-induced damage. Although it was reported that high-LET heavy ion radiation (>85 keV/μm) could cause p53-independent cell death in some cancer cell lines, whether there is any radioprotective effect of the p53 regulatory agents against the high-LET radiation injury in vivo is still unclear. In the present study, we verified the efficacy of these agents on bone marrow and intestinal damages induced by high-LET heavy-ion irradiation in mice. We used a carbon-beam (14 keV/μm) that was shown to induce a p53-dependent effect and an iron-beam (189 keV/μm) that was shown to induce a p53-independent effect in a previous study. Vanadate significantly improved 60-day survival rate in mice treated with total-body carbon-ion (p < 0.0001) or iron-ion (p < 0.05) irradiation, indicating its effective protection of the hematopoietic system from radiation injury after high-LET irradiation over 85 keV/μm. 5CHQ also significantly increased the survival rate after abdominal carbon-ion (p < 0.02), but not iron-ion irradiation, suggesting the moderate relief of the intestinal damage. These results demonstrated the effectiveness of p53 regulators on acute radiation syndrome induced by high-LET radiation.
Highlights
In recent years, several molecular target drugs have been developed for reducing acute radiation toxicities [1,2,3,4,5,6,7,8]
The effects of these radioprotectors have been demonstrated by experiments with low-LET radiation, we speculated that such cell death-regulating agents were effective for protection against particle beam injury, because their radioprotective efficacies do not depend on a radical scavenging action, which is mainly effective for radiation injury caused by indirect action [9]
These data clearly demonstrate that vanadate has a protective effect against the bone marrow death induced by carbon-beam total-body irradiation (TBI), while that it is ineffective against the intestinal death induced by carbon-beam abdominal irradiation (ABI)
Summary
Several molecular target drugs have been developed for reducing acute radiation toxicities [1,2,3,4,5,6,7,8]. Radioprotection by p53 Regulatory Agents dose, cell death-regulating agents are expected as one of the non-invasive measures to reduce adverse events from occurring in organs at risk (OAR). This is especially necessary to protect OAR close to the tumor and to further improve hypofractionated regimens to increase the dose per fraction while suppressing the side effects of acute injury [10,11,12,13]. These HZE particles make up only 1% of GCRs, they are high-LET particle radiations They contribute to 21% of the estimated ionizing dose equivalent from GCR exposure during interplanetary missions in deep space and contribute significantly to the overall biological impact of cosmic rays [16]
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