抗辐射药物研究进展

李 敏，赵德华，王继生*

·综述·

抗辐射药物研究进展

李 敏1，赵德华2，王继生1*

抗辐射药物主要用于保护暴露电离辐射环境下的机体，同时不影响肿瘤细胞对放射治疗的敏感性。按照来源分类主要包括天然抗辐射药物与非天然抗辐射药物；按照化学结构分类主要包括维生素类、黄酮类、甲基黄嘌呤类、巯基类、氮氧自由基类、二苯并咪唑类、富勒烯及其他新型化合物。本文对不同来源与结构的抗辐射药物进行综述，以期为寻找更理想的抗辐射药物提供参考依据。

辐射；抗辐射药物；结构

0 引言

电离辐射是一种主要由电磁波(X、γ射线)或粒子(α、β、中子)组成的能量，可通过各种途径(微循环障碍、细胞凋亡、癌变、DNA突变等)对机体的造血功能[1]、消化系统[2-3]及免疫系统[4]造成显著影响。其中，急性辐射综合征[5](Acute radiation syndrome，ARS)是一种短时间内高能量射线照射全身或局部而引起的疾病，其主要损伤部位为造血系统、胃肠道系统，可导致神经压迫综合征，严重时可危及生命。为了降低电离辐射对人体造成的损伤，抗辐射药物的开发和利用已成为辐射保护及损伤救治的研究热点。而理想的抗辐射药物应该在保护正常细胞的同时，不影响肿瘤细胞对射线的敏感性[5-6]。为了解抗辐射药物的研究现状，本文对不同作用机制的抗辐射药物进行综述，以期为抗辐射药物的开发与应用提供理论依据。

1 天然来源的抗辐射药物

1.1 食物中的抗氧化剂 维生素A、维生素C、维生素E通过阻断自由基引起的链式反应而达到辐射防护的作用。Rostami等[7]通过体外微核试验证实维生素C能够降低6 mV的X射线辐照下人外周血淋巴细胞诱导产生的遗传毒性。Mathew等[8]对抗坏血酸葡萄糖苷(Ascorbic acid monoglucoside，AsAG)进行脉冲辐射分解试验表明，AsAG通过清除自由基起到保护作用，25 Gy γ辐照前对小鼠使用AsAG能够保护肝组织中脂质过氧化，同时，对辐射后质粒DNA进行的琼脂糖凝胶电泳试验的结果表明，AsAG能够保护质粒pBR322 DNA免受γ辐射诱导链断裂。Srinivasan等[9]研究表明，维生素E单独使用或与WR-3689(氨基硫醇类化合物)联用能增加辐照小鼠的生存率。Suman等[10]报道，γ-生育酚(Gamma tocotrienol，GT3)能够上调抗凋亡基因表达，提高小肠细胞生存率，从而起到降低放射诱导的胃肠道毒性反应。另一个抗氧化剂-硒元素，其辐射防护作用已经在实验室和临床得到了证实[11-12]。Sieber等[13]发现，高剂量的硒膳食补充可减轻辐照大鼠的放射性肾损伤，进一步研究发现，连续4个月补充200 μg/d 亚硒酸钠或硒-L-蛋氨酸能够大幅缓解辐射肾病，降低脑外伤的BUN水平(从115 mg/mL降至34 mg/mL)及组织病理学异常的发生率[14]。

1.2 褪黑素 褪黑素是松果腺分泌的激素，能够有效清除羟基和过氧化物自由基[15]。Shirazi等[16]研究表明，褪黑素具有辐射防护的功能，可提高辐照大鼠的生存率，Koc等[17]提出，褪黑激素可以防止γ射线导致大鼠出现肝组织氧化损伤。Shirazi等[16]在放射前或放射后给予患者褪黑素，发现褪黑素可通过降低丙二醛水平和提高谷胱甘肽水平，来降低肝脏损伤的发生率及损伤程度。Fernández-Gil等[18]研究表明，褪黑素与降低炎症反应，抑制NF-κB信号通路的激活及 NLRP3炎性通路的活化有关，而口服褪黑素凝胶可降低放疗患者发生胃肠综合征的概率。此外，相关研究表明，无论是单独使用褪黑素还是与其他药物联用，放疗患者的临床预后都会得到一定的提高[19-20]。

1.4 甲基黄嘌呤 甲基黄嘌呤包括己酮可可碱、咖啡因、可可碱和茶碱。Berbée等[27]研究表明，己酮可可碱单用或与γ-生育三烯酚联合用药可缓解患者造血系统损伤。George等[28]的临床随机对照试验显示，己酮可可碱和维生素E能预防高危乳腺癌患者放疗后出现肺纤维化。Asadullina等[29]利用流式细胞微核试验发现，肌苷-5′-磷酸能够减少DNA损伤来起到辐射保护作用。另外的一项研究表明，在放射前或放射后给予咖啡因(80～100 mg/kg)可减少小鼠出现放射性皮肤损伤，且不影响肿瘤细胞对放射的敏感性[28]。

1.5 草本植物类的抗辐射药物 植物来源的天然化合物具有毒性低、耐受性好的特点[30]，因此成为抗辐射药物的研究热点，相关研究表明，姜黄、乌梅、木苹果(也称印度桔橘)、薄荷、黄绿茶、红茶多酚、银杏提取物、葡萄提取物、大豆异黄酮、生姜等都具有一定的抗辐射作用[31-32]。Zbikowska等[33]研究发现，辣木根的多酚类化合物可防止γ射线辐照造成的光氧化损伤。Szejk等[34]研究表明，蔷薇科和菊科植物的多酚提取物能减少辐射引起的脂质过氧化反应及DNA损伤。而Kim等[35]研究发现，100 mg/kg人参苷可通过对氧化应激和细胞凋亡的调控来防止放射性肝损伤的发生。Ma等[36]研究显示，阿魏酸可对抗辐射诱发的氧化应激反应。此外，另一项研究结果表明，川芎嗪可通过调控NF-κB通路来保护淋巴细胞免受辐射诱导的细胞凋亡[37]。

2 非天然来源的抗辐射药物

2.1 巯基类化合物的抗辐射药物 Patt等[38]首次报道半胱氨酸(含-SH)具有辐射防护作用，随后，研究者们合成了一系列含氨基硫醇基团的化合物并证实了其具有较强的抗辐射活性。其中最成功的化合物是氨磷汀[39](WR-2721)，氨磷汀为前体药物，在体内通过去磷酸化转化成活性形式WR-106来发挥药理作用，并于1995年被美国FDA批准用于放疗保护和化疗保护。Maisin等[40]报道，尼莫地平10 mg/kg联合WR-151327(氨基硫醇类化合物)200 mg/kg的辐射保护作用要强于单用WR-151327。此外，采用肌肉组织氧分压的电子顺磁共振光谱和成像技术来测量组织中的血氧饱和度，结果发现，氨磷汀可以降低肌肉和肿瘤组织的氧分压，表明氧分压的降低可能有助于氨磷汀发挥辐射防护作用[41-42]。

PrC-210是氨基硫醇类似物，对全身致死剂量的射线辐照具有抗辐射活性[43]。体外研究表明，PrC-210可抑制人成纤维细胞的生长并能抑制p21蛋白的表达，p21蛋白主要调节细胞周期由G1期向S期转化[44]。在动物模型试验中，研究结果表明，在皮肤照射前腹腔或局部给予PrC-210可防止2～3级的放射性皮炎[43]。此外，Copp等[45]研究结果显示，腹腔或口服给予辐照小鼠/大鼠PrC-210，辐照小鼠/大鼠的存活率为100%，且临床相关剂量下的PrC-210并未出现恶心、呕吐和低血压等毒副反应。尽管氨磷汀的剂量系数为1.6时，其恶心、呕吐和低血压的发生率为100%，但迄今为止，氨磷汀仍被视为最成功的抗辐射药物并被FDA批准用于放疗患者。与之相比，PrC-210在剂量系数为1.6时未出现任何的毒副反应。提示PrC-210具有开发成为新辐射防护剂的潜力和临床应用价值。

2.2 非巯基类化合物的辐射保护剂

2.2.1 氮氧自由基 氮氧自由基是由C、N、O、H原子组成的一种稳定的自由基化合物，可通过与多种配体结合来为正常细胞提供辐射保护作用[46]，其主要作用机制为清除超氧化物阴离子，降低过渡金属氧化性及抑制脂质过氧化反应。目前已有一系列的低分子量氮氧自由基得到合成，并且其抗辐射活性得到证实[47]，其中2个代表性的化合物分别为Tempol(4-羟基-2,2,6,6-四甲基哌啶氮氧自由基)和NITR(2-R-4,4,5,5-四甲基咪唑啉-3-氧化-1-氧基自由基)。Cotrim等[48]研究发现，Tempol 在保护唾液腺的同时还不影响肿瘤细胞对射线的敏感性。最近，Davis等[49]发现了一种比Tempol具有更高效的辐射防护作用和血脑穿透作用的氮氧自由基化合物。

2.2.2 二苯并咪唑 二苯并咪唑杂环芳香族化合物是由2个咪唑基和1个酚基构成，它通过作用于DNA来显示出抗辐射活性[50]。研究表明，双苯并咪唑衍生物Hoechst-33342(H-342)和Hoechst-33258可抑制辐照小鼠微核的形成，而静脉注射80 mg/kg 的H-342可抑制细胞的凋亡反应和防止早期辐射导致的内皮细胞损伤[51]。Martin等[52]成功合成了methylproamine，一个新的Hoechst 33342类似物，其辐射防护作用大约是WR1065的100倍。Tawar等[47]利用动物模型证明了DMA和TBZ(新型毒副作用低的苯并咪唑衍生物)能引起核固缩，清除自由基，防止辐射导致的DNA损伤。进一步研究表明，DMA可通过激活NF-κB/IKK通路而显示出抗辐射活性[53]。

2.2.3 富勒烯 富勒烯是碳的同素异形体，由不同数目的碳原子组成。研究表明，水溶性的富勒烯具有清除活性氧(ROS)[54]和自由基[55]的作用。Theriot等[56]采用动物模型实验研究表明，C60的富勒烯化合物DF-1比氨磷汀具有更显著的辐射防护作用和更低的毒副反应。另外，Daroczi等[57]进行的斑马鱼模型试验结果也表明DF-1具有较好的抗辐射活性。

2.2.4 超氧化物歧化酶-金属配合物 超氧化物歧化酶(SOD)可与铜、锌、锰结合，从而以金属-SOD的形式存在，可通过加速氧自由基转化为O2和H2O2来清除氧自由基[55]。Borrelli等[58]采用基因疗法重组活性锰超氧化物歧化酶(Mn-SOD)进行体内试验，发现其不仅对正常细胞具有辐射保护作用，并且能够增强肿瘤细胞对射线的敏感性。虽然临床前相关研究表明SOD可以作为一种有效的抗辐射药物，但因其半衰期较短、分子量高而无法自由穿过细胞膜，从而导致其临床应用受到限制[59]。而Liu等[60]成功合成了肝素-SOD配合物，该配合物能显著延长血浆中SOD的半衰期。另外一种SOD类似物M40403[61]也可保护小鼠免受致命辐射剂量的伤害。

2.2.5 HMG-CoA还原酶抑制剂 HMG-CoA还原酶抑制剂(他汀类药物)是甲羟戊酸途径的限速酶，是由胆固醇和其他类异戊二烯合成。Fritz等[62]研究发现，HMG-CoA还原酶抑制剂具有一定的抗辐射作用。Berbée等[63]研究发现，γ-生育三烯酸可防止辐照小鼠出现放射性肠炎，还可通过调节HMG-CoA还原酶来抑制血管的过氧化作用。Nübel等[64]采用原代人脐静脉内皮细胞分析洛伐他汀对IR引起的细胞毒性，发现洛伐他汀在浓度为1 μmol/L 时，对人血管内皮细胞具有抗辐射和抗细胞凋亡的作用。

2.2.6 Toll受体5激动剂(CBLB502) CBLB502是从沙门氏菌鞭毛蛋白中提取并通过药理优化实验筛选出的多肽类药物，是一种Toll样受体5激动剂，目前，各种体内实验均显示其具有较好的辐射防护作用[6]。Burdelya等[65]研究发现，单剂量的CBLB502(0.2 mg/kg)可防止辐照小鼠(10、13 Gy)出现胃肠系统综合征和造血系统综合征，且并未影响肿瘤细胞对放射的敏感性。进一步研究表明，CBLB502可通过激活NF-κB和STAT3κ信号转导通路来保护辐照小鼠免受致死性的辐射伤害[65]。另外，Burdelya等[66]发现，CBLB502还可保护辐照小鼠出现由辐射引起的皮炎和口腔黏膜炎。同时，Wang等[67]研究表明，CBLB502可防止辐照小鼠出现放射性肺炎及肺纤维化。

2.2.7 其他新型抗辐射药物 Singh等[68]研究表明，CBLB613(TLR2/6激动剂)对致死剂量的60Co γ射线具有辐射保护作用。而Johnson等[69]研究发现，选择性CDK4/6抑制剂(PD033291)可减轻辐照小鼠的造血系统毒性，并能提高小鼠的存活率。Gluzman-Poltorak等[70]提出，重组人IL-12能降低辐射导致的造血系统毒性和感染，从而显著提高猕猴的生存率。Ma等[71]研究表明，成纤维细胞生长因子肽可促进体内骨髓造血干细胞的恢复。也有报道，粒细胞和巨噬细胞的集落刺激因子具有抗辐射作用[72]。同时，Doan等[73]研究显示，表皮生长因子可提高全身照射后造血系统的恢复能力。此外，有报道，格尔德霉素类似物(17-DMAG)可增加骨髓中CD34、CD44以及血清中性粒细胞集落刺激因子水平，上调Lgr5的表达，激活Lgr5肠隐窝干细胞，从而加速绒毛的修复和恢复[74]。目前，包括CBLB502、5-雄烯二醇、Recilisib/On01210、BIO300、Orbeshield、Hemamax、Neupogen在内的7个抗辐射药物已经被FDA列为新药研究项目[75]，具有良好的临床应用前景。

3 总结及展望

综上所述，理想的抗辐射药物需要具备以下3个特点：①选择性强，即对正常细胞具有较强的辐射防护作用，而对肿瘤细胞的影响作用较弱；②毒副反应低，患者可耐受，能在临床广泛使用；③易获得，成本低。目前被FDA批准用于放疗防护的氨磷汀和帕利，虽然疗效确切，但毒副反应较大，患者难以耐受，因此，在临床上难以被广泛应用，故需要寻找更加安全、有效且经济的抗辐射药物来满足临床的需求。而天然与生物来源的药物与传统的化学合成药物相比，具有抗辐射活性高、选择性强、毒副反应低的优点，因此，可能会作为新型的抗辐射药物而具有良好的临床应用前景。

[1] Wen S,Dooner M,Cheng Y,et al.Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells[J].Leukemia,2016,30(11):2221-2231.

[2] Shea-Donohue T,Fasano A,Zhao A,et al.Mechanisms involved in the development of the chronic gastrointestinal syndrome in nonhuman primates after total-body irradiation with bone marrow shielding[J].Radiat Res,2016,185(6):591-603.

[3] Yeoh EK,Krol R,Dhillon VS,et al.Predictors of radiation-induced gastrointestinal morbidity:a prospective,longitudinal study following radiotherapy for carcinoma of the prostate[J].Acta Oncol,2016,55(5):604-610.

[4] Xiao M.The role of proinflammatory cytokine Interleukin-18 in radiation injury[J].Health Phys,2016,111(2):212-217.

[5] Kamran MZ,Ranjan A,Kaur N,et al.Radioprotective agents:strategies and translational advances[J].Med Res Rev,2016,36(3):461-493.

[6] Burdelya LG,Krivokrysenko VI,Tallant TC,et al.An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models[J].Science,2008,320(5873):226-230.

[7] Rostami A,Moosavi SA,Dianat MH,et al.Micronuclei assessment of the radioprotective effects of melatonin and vitamin c in human lymphocytes[J].Cell J,2016,18(1):46-51.

[8] Mathew D,Nair CK,Jacob JA,et al.Ascorbic acid monoglucoside as antioxidant and radioprotector[J].J Radiat Res,2007,48(5):369-376.

[9] Srinivasan V,Weiss JF.Radioprotection by vitamin E:injectable vitamin E administered alone or with WR-3689 enhances survival of irradiated mice[J].Int J Radiat Oncol Biol Phys,1992,23(4):841-845.

[10] Suman S,Datta K,Chakraborty K,et al.Gamma tocotrienol,a potent radioprotector,preferentially upregulates expression of anti-apoptotic genes to promote intestinal cell survival[J].Food Chem Toxicol,2013,60:488-496.

[11] Roman M,Jitaru P,Barbante C.Selenium biochemistry and its role for human health[J].Metallomics,2014,6(1):25-54.

[12] Micke O,Schomburg L,Buentzel J,et al.Selenium in oncology:from chemistry to clinics[J].Molecules,2009,14(10):3975-3988.

[13] Sieber F,Muir SA,Cohen EP,et al.High-dose selenium for the mitigation of radiation injury:a pilot study in a rat model[J].Radiat Res,2009,171(3):368-373.

[14] Franca CA,Nogueira CR,Ramalho A,et al.Serum levels of selenium in patients with breast cancer before and after treatment of external beam radiotherapy[J].Ann Oncol,2011,22(5):1109-1112.

[15] Reiter RJ,Manchester LC,Tan DX.Neurotoxins:free radical mechanisms and melatonin protection[J].Curr Neuropharmacol,2010,8(3):194-210.

[16] Shirazi A,Mihandoost E,Mohseni M,et al.Radio-protective effects of melatonin against irradiation-induced oxidative damage in rat peripheral blood[J].Phys Med,2013,29(1):65-74.

[17] Koc M,Taysi S,Buyukokuroglu ME,et al.Melatonin protects rat liver against irradiation-induced oxidative injury[J].J Radiat Res,2003,44(3):211-215.

[18] Fernández-Gil B,Moneim AE,Ortiz F,et al.Melatonin protects rats from radiotherapy-induced small intestine toxicity[J].PLoS One,2017,12(4):e0174474.

[19] Najafi M,Shirazi A,Motevaseli E,et al.Melatonin as an anti-inflammatory agent in radiotherapy[J].Inflammopharmacology,2017,25(4):403-413.

[20] Najafi M,Shirazi A,Motevaseli E,et al.The melatonin immunomodulatory actions in radiotherapy[J].Biophys Rev,2017,9(2):139-148.

[21] Kandaswami C,Middleton E.Free radical scavenging and antioxidant activity of plant flavonoids[J].Adv Exp Med Biol,1994,366:351-376.

[23] Panat NA,Maurya DK,Ghaskadbi SS,et al.Troxerutin,a plant flavonoid,protects cells against oxidative stress-induced cell death through radical scavenging mechanism[J].Food Chem,2016,194:32-45.

[24] Abernathy LM,Fountain MD,Rothstein SE,et al.Soy isoflavones promote radioprotection of normal lung tissue by inhibition of radiation-induced activation of macrophages and neutrophils[J].J Thorac Oncol,2015,10(12):1703-1712.

[25] Jagetia GC,Venkatesha VA,Reddy TK.Naringin,a citrus flavonone,protects against radiation-induced chromosome damage in mouse bone marrow[J].Mutagenesis,2003,18(4):337-343.

[26] Yun KL,Wang ZY.Target/signalling pathways of natural plant-derived radioprotective agents from treatment to potential candidates:a reverse thought on anti-tumour drugs[J].Biomed Pharmacother,2017,91:1122-1151.

[27] Berbée M,Fu Q,Garg S,et al.Pentoxifylline enhances the radioprotective properties of γ-tocotrienol:differential effects on the hematopoietic,gastrointestinal and vascular systems[J].Radiat Res,2011,175(3):297-306.

[28] George KC,Hebbar SA,Kale SP,et al.Caffeine protects mice against whole-body lethal dose of gamma-irradiation[J].J Radiol Prot,1999,19(2):171-176.

[29] Asadullina NR,Usacheva AM,Gudkov SV.Protection of mice against X-ray injuries by the post-irradiation administration of inosine-5′-monophosphate[J].J Radiat Res,2012,53(2):211-216.

[30] Kma L.Plant extracts and plant-derived compounds:promising players in a countermeasure strategy against radiological exposure[J].Asian Pac J Cancer Prev,2014,15(6):2405-2425.

[31] Arora R,Gupta D,Chawla R,et al.Radioprotection by plant products:present status and future prospects[J].Phytother Res,2005,19(1):1-22.

[32] Johnke RM,Sattler JA,Allison RR.Radioprotective agents for radiation therapy:future trends[J].Future Oncol,2014,10(15):2345-2357.

[33] Zbikowska HM,Szejk M,Saluk J,et al.Polyphenolic-polysaccharide conjugates from plants of Rosaceae/Asteraceae family as potential radioprotectors[J].Int J Biol Macromol,2016,86:329-337.

[34] Szejk M,Poplawski T,Sarnik J,et al.Polyphenolic glycoconjugates from medical plants of Rosaceae/Asteraceae family protect human lymphocytes against γ-radiation-induced damage[J].Int J Biol Macromol,2017,94(Pt A):585-593.

[35] Kim HG,Jang SS,Lee JS,et al.Panax ginseng Meyer prevents radiation-induced liver injury via modulation of oxidative stress and apoptosis[J].J Ginseng Res,2017,41(2):159-168.

[36] Ma ZC,Hong Q,Wang YG,et al.Ferulic acid protects lymphocytes from radiation-predisposed oxidative stress through extracellular regulated kinase[J].Int J Radiat Biol,2011,87(2):130-140.

[37] Wang XY,Ma ZC,Wang YG,et al.Tetramethylpyrazine protects lymphocytes from radiation-induced apoptosis through nuclear factor-κB[J].Chin J Nat Med,2014,12(10):730-737.

[38] Patt HM,Tyree EB,Straube RL,et al.Cysteine protection against X irradiation[J].Science,1949,110(2852):213-214.

[39] Kouvaris JR,Kouloulias VE,Vlahos LJ.Amifostine:the first selective-target and broad-spectrum radioprotector[J].Oncologist,2007,12(6):738-747.

[40] Maisin JR,Albert C,Henry A.Reduction of short-term radiation lethality by biological response modifiers given alone or in association with other chemical protectors[J].Radiat Res,1993,135(3):332-337.

[41] Koukourakis MI,Giatromanolaki A,Zois CE,et al.Normal tissue radioprotection by amifostine via Warburg-type effects[J].Sci Rep,2016,6:30986.

[42] Ueno M,Matsumoto S,Matsumoto A,et al.Effect of amifostine,a radiation-protecting drug,on oxygen concentration in tissue measured by EPR oximetry and imaging[J].J Clin Biochem Nutr,2017,60(3):151-155.

[43] Peebles DD,Soref CM,Copp RR,et al.ROS-scavenger and radioprotective efficacy of the new PrC-210 aminothiol[J].Radiat Res,2012,178(1):57-68.

[44] Soref CM,Hacker TA,Fahl WE.A new orally active,aminothiol radioprotector-free of nausea and hypotension side effects at its highest radioprotective doses[J].Int J Radiat Oncol Biol Phys,2012,82(5):e701-e707.

[45] Copp RR,Peebles DD,Soref CM,et al.Radioprotective efficacy and toxicity of a new family of aminothiol analogs[J].Int J Radiat Biol,2013,89(7):485-492.

[46] Hahn SM,Krishna CM,Samuni A,et al.Potential use of nitroxides in radiation oncology[J].Cancer Res,1994,54(7 Suppl):2006s-2010s.

[47] Citrin D,Cotrim AP,Hyodo F,et al.Radioprotectors and mitigators of radiation-induced normal tissue injury[J].Oncologist,2010,15(4):360-371.

[48] Cotrim AP,Hyodo F,Matsumoto K,et al.Differential radiation protection of salivary glands versus tumor by Tempol with accompanying tissue assessment of Tempol by magnetic resonance imaging[J].Clin Cancer Res,2007,13(16):4928-4933.

[49] Davis RM,Sowers AL,DeGraff W,et al.A novel nitroxide is an effective brain redox imaging contrast agent and in vivo radioprotector[J].Free Radic Biol Med,2011,51(3):780-790.

[50] Bailly C,Chessari G,Carrasco C,et al.Sequence-specific minor groove binding by bis-benzimidazoles:water molecules in ligand recognition[J].Nucleic Acids Res,2003,31(5):1514-1524.

[51] Singh SP,Jayanth VR,Chandna S,et al.Radioprotective effects of DNA ligands Hoechst-33342 and 33258 in whole body irradiated mice[J].Indian J Exp Biol,1998,36(4):375-384.

[52] Martin RF,Broadhurst S,Reum ME,et al.In vitro studies with methylproamine:a potent new radioprotector[J].Cancer Res,2004,64(3):1067-1070.

[53] Kaur N,Ranjan A,Tiwari V,et al.DMA,a bisbenzimidazole,offers radioprotection by promoting NFκB transactivation through NIK/IKK in human glioma cells[J].PLoS One,2012,7(6):e39426.

[54] Andrievsky GV,Bruskov VI,Tykhomyrov AA,et al.Peculiarities of the antioxidant and radioprotective effects of hydrated C60 fullerene nanostuctures in vitro and in vivo[J].Free Radic Biol Med,2009,47(6):786-793.

[55] Yin JJ,Lao F,Fu PP,et al.The scavenging of reactive oxygen species and the potential for cell protection by functionalized fullerene materials[J].Biomaterials,2009,30(4):611-621.

[56] Theriot CA,Casey RC,Moore VC,et al.Dendro[C(60)]fullerene DF-1 provides radioprotection to radiosensitive mammalian cells[J].Radiat Environ Biophys,2010,49(3):437-445.

[57] Daroczi B,Kari G,McAleer MF,et al.In vivo radioprotection by the fullerene nanoparticle DF-1 as assessed in a zebrafish model[J].Clin Cancer Res,2006,12(23):7086-7091.

[58] Borrelli A,Schiattarella A,Mancini R,et al.A recombinant MnSOD is radioprotective for normal cells and radiosensitizing for tumor cells[J].Free Radic Biol Med,2009,46(1):110-116.

[59] Huang XJ,Song CX,Zhong CQ,et al.Research progress in the radioprotective effect of superoxide dismutase[J].Drug Discov Ther,2012,6(4):169-177.

[60] Liu J,Zhao T,Tan H,et al.Pharmacokinetic analysis of in vivo disposition of heparin-superoxide dismutase[J].Biomed Pharmacother,2010,64(10):686-691.

[61] Thompson JS,Chu Y,Glass J,et al.The manganese superoxide dismutase mimetic,M40403,protects adult mice from lethal total body irradiation[J].Free Radic Res,2010,44(5):529-540.

[62] Fritz G,Henninger C,Huelsenbeck J.Potential use of HMG-CoA reductase inhibitors (statins) as radioprotective agents[J].Br Med Bull,2011,97:17-26.

[63] Berbée M,Fu Q,Boerma M,et al.gamma-Tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative stress after total-body irradiation by an HMG-CoA reductase-dependent mechanism[J].Radiat Res,2009,171(5):596-605.

[64] Nübel T,Damrot J,Roos WP,et al.Lovastatin protects human endothelial cells from killing by ionizing radiation without impairing induction and repair of DNA double-strand breaks[J].Clin Cancer Res,2006,12(3 Pt 1):933-939.

[65] Burdelya LG,Brackett CM,Kojouharov B,et al.Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist[J].Proc Natl Acad Sci U S A,2013,110(20):E1857-E1866.

[66] Burdelya LG,Gleiberman AS,Toshkov I,et al.Toll-like receptor 5 agonist protects mice from dermatitis and oral mucositis caused by local radiation:implications for head-and-neck cancer radiotherapy[J].Int J Radiat Oncol Biol Phys,2012,83(1):228-234.

[67] Wang ZD,Qiao YL,Tian XF,et al.Toll-like receptor 5 agonism protects mice from radiation pneumonitis and pulmonary fibrosis[J].Asian Pac J Cancer Prev,2012,13(9):4763-4767.

[68] Singh VK,Ducey EJ,Fatanmi OO,et al.CBLB613:a TLR 2/6 agonist,natural lipopeptide of Mycoplasma arginini,as a novel radiation countermeasure[J].Radiat Res,2012,177(5):628-642.

[69] Johnson SM,Torrice CD,Bell JF,et al.Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition[J].J Clin Invest,2010,120(7):2528-2536.

[70] Gluzman-Poltorak Z,Mendonca SR,Vainstein V,et al.Randomized comparison of single dose of recombinant human IL-12 versus placebo for restoration of hematopoiesis and improved survival in rhesus monkeys exposed to lethal radiation[J].J Hematol Oncol,2014,7:31.

[71] Ma J,Hou Y,Han D,et al.Fibroblast growth factor-peptide promotes bone marrow recovery after irradiation[J].Adv Exp Med Biol,2013,765:155-161.

[72] Singh VK,Newman VL,Seed TM.Colony-stimulating factors for the treatment of the hematopoietic component of the acute radiation syndrome (H-ARS):a review[J].Cytokine,2015,71(1):22-37.

[73] Doan PL,Himburg HA,Helms K,et al.Epidermal growth factor regulates hematopoietic regeneration after radiation injury[J].Nat Med,2013,19(3):295-304.

[74] Lu X,Nurmemet D,Bolduc DL,et al.Radioprotective effects of oral 17-dimethylaminoethylamino-17-demethoxygeldanamycin in mice:bone marrow and small intestine[J].Cell Biosci,2013,3(1):36.

[75] Singh VK,Romaine PL,Seed TM.Medical countermeasures for radiation exposure and related injuries:characterization of medicines,FDA-approval status and inclusion into the strategic national stockpile[J].Health Phys,2015,108(6):607-630.

Researchprogressonanti-radiationdrugs

LI Min1,ZHAO De-hua2,WANG Ji-sheng1*

(1.Department of Pharmacy,Southwest University of Medical Sciences,Luzhou 646000,China;2.the Third Hospital of Mianyang,Mianyang 621000,China)

The anti-radiation drugs are mainly used to protect the body that are exposed to radiation environment and do not affect the tumor sensitivity to radiation therapy.The anti-radiation drugs mainly include natural and non-natural sources according to the sources,or vitamins,flavones,methylxanthine,thiol,nitrogen and oxygen free radicals,benzimidazole,fullerene and other new compounds according to the chemical constitution.This paper summarized the anti-radiation drugs with different sources and structures,in order to provide references for finding more ideal anti-radiation drugs.

Radiation;Anti-radiation drugs;Structure

2017-05-02

1.西南医科大学药学院，四川 泸州 646000；2.绵阳市第三人民医院，四川 绵阳 621000

四川省科技厅资助项目(2014JY0058)

*

10.14053/j.cnki.ppcr.201712023