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RNA synthesis inhibitors and protein synthesis inhibitors are useful for investigating whether biological events with unknown mechanisms require transcription or translation; however, the dependence of RNA synthesis has been difficult to verify because many RNA synthesis inhibitors cause adverse events that trigger a p53 response. In this study, we screened a library containing 9600 core compounds and obtained STK160830 that shows anti-apoptotic effects in irradiated wild-type-p53-bearing human T-cell leukemia MOLT-4 cells and murine thymocytes. In many of the p53-impaired cells and p53-knockdown cells tested, STK160830 did not show a remarkable anti-apoptotic effect, suggesting that the anti-apoptotic activity is p53-dependent. In the expression analysis of p53, p53-target gene products, and reference proteins by immunoblotting, STK160830 down-regulated the expression of many of the proteins examined, and the downregulation correlated strongly with its inhibitory effect on cell death. mRNA expression analyses by qPCR and nascent RNA capture kit revealed that STK160830 showed a decreased mRNA expression, which was similar to that induced by the RNA synthesis inhibitor actinomycin D but differed to some extent. Furthermore, unlike other RNA synthesis inhibitors such as actinomycin D, p53 accumulation by STK160830 alone was negligible, and a DNA melting-curve analysis showed very weak DNA-intercalating activity, indicating that STK160830 is a useful inhibitor for RNA synthesis without triggering p53-mediated damage responses.

Purpose: Our previous study indicated that sodium orthovanadate (vanadate), a strong inhibitor of p53, effectively suppressed the lethality from the hematopoietic (HP) and gastrointestinal (GI) syndromes after 12 Gy total-body irradiation (TBI) in mice. This conclusion, however, was inconsistent with the fact that p53 plays a radioprotective role in the intestinal epithelium. The death after TBI of around 12 Gy was attributed to a combined effect of HP and GI syndromes. To verify the effect from prophylactic administration of p53 inhibitor on protection of HP and GI syndromes, in this study, the radioprotective effects from vanadate were investigated in TBI and lower half-body irradiation (partial-body irradiation: PBI) mouse models. Methods: Female ICR mice were given a single injection of vanadate or vehicle, followed by a lethal dose of TBI or PBI. Radioprotective effects of vanadate against the irradiations were evaluated by analyzing survival rate, body weight, hematopoietic parameters, and histological changes in the bone marrow and intestinal epithelium. Results: TBI-induced HP syndrome was effectively suppressed by vanadate treatment. After TBI, the vanadate-treated mice retained better bone marrow cellularity and showed markedly higher survival rate compared to the vehicle-treated animals. In contrast, vanadate did not relieve loss of intestinal crypts and failed to rescue mice from GI death after PBI. Conclusion: Vanadate is a p53 inhibitor that has been shown to be beneficial as a radiation protective agent against HP but was not effective in protecting against acute GI radiation injury.

Radiation damage to normal tissues is a serious concern in radiation therapy. Advances in radiotherapeutic technology have improved the dose distribution of the target volumes and risk organs, but damage to risk organs that are located within the irradiation field still limits the allowable prescription dose. To overcome this dose-limiting toxicity, and to further improve the efficacy of radiotherapy, the development of drugs that protect normal tissues but not cancer tissues from the effects of radiation are expected to be developed based on molecular target-based drugs. p53 is a well-known transcription factor that is closely associated with radiation-induced cell death. In radiation-injured tissues, p53 induces apoptosis in hematopoietic lineages, whereas it plays a radioprotective role in the gastrointestinal epithelium. These facts suggest that p53 inhibitor would be effective for radioprotection of the hematopoietic system, and that a drug that upregulates the radioprotective functions of p53 would enhance the radioresistance of gastrointestinal tissues. In this review, we summarize recent progress regarding the prevention of radiation injury by regulating p53 and provide new strategic insights into the development of radioprotectors in radiotherapy.

岡山大学と日本原子力研究開発機構人形峠環境技術センターは、低線量放射線域でのラドン吸入に起因する影響効果にかかわる共同研究を実施している。岡山大学病院三朝医療センターは、臨床的な知見に基づく研究課題設定を、岡山大学大学院保健学研究科は研究管理及び生体応答評価を、原子力機構人形峠はラドン吸入試験設備の開発、ラドン濃度の制御、ラドンの体内挙動・線量評価をそれぞれ分担することとした。平成19年度から平成23年度は以下の成果を得た。(1)本研究の課題設定にあたり、低線量域でのラドンの影響効果について文献調査した。(2)大規模な小動物のラドン吸入試験を目的とした国内初の大規模設備を開発した。(3)ラドンによる諸臓器の抗酸化機能の変化を知るうえで最も基本的な条件となる、ラドン濃度と吸入時間の関係について網羅的に検討した。(4)ラドン吸入に臓器中の抗酸化機能を亢進する効果を確認したことから、症状緩和が期待できる酸化障害への効果について疾患モデルマウスによる検討を行い、肝臓などでのアルコール等誘導酸化障害やI型糖尿病に対する抑制効果を確認した。(5)吸入ラドンによる生体応答を定量的に議論するため、吸入ラドンの体内動態を把握し、諸臓器・組織の吸収線量の評価方法について検討した。, Okayama University and the Japan Atomic Energy Agency (JAEA) have carried out the collaborative study of physiological effects of inhaled radon for the low-dose range. From 2007 to 2011, the following results were obtained. (1) Literature on effects of radon for the low-dose range was surveyed to determine the present tasks. (2) The first Japanese large-scale facility was developed for radon inhalation experiments with small animals. (3) Relationships between radon concentration and inhalation time were widely examined to understand the change in antioxidative functions due to radon, which are the most basic parameters. (4) Inhibitory effects of radon on oxidative damages were observed using model mice with reactive oxygen- or free radical-related diseases like alcohol-induced oxidative damages and type I diabetes. (5) In order to discuss biological responses quantitatively following radon inhalation, the biokinetics of inhaled radon was examined and the model for calculation of absorbed doses for organs and tissues was obtained., 著者所属: 日本原子力研究開発機構(JAEA), JAEA-Research 2013-005