辐射防护药的研究开始于上个世纪五十年代,经过科学家的不断努力,发现了一些效果相对较好的药物,如氨磷汀、硝基氧和粒细胞集落刺激因子(granulocyte colony-stimulating factor,G-CSF)等等。但始终没有发现一种能够应用于临床的抗辐射作用优良、不良反应小和安全性高的药物。近些年来,随着基因组学、蛋白组学和免疫学等学科的高速发展,科研人员对于辐射防护药的研究有了新的认识和不小突破。例如近年来的一些酶抑制剂类小分子药物,如组蛋白脱乙酰酶抑制剂,已成为抗辐射药物的研究热点;具有较高的开发价值且获得了美国食品药品监督管理局(food and drug administration,FDA)临床研究授权的HemaMax,以及激素类的Neumune已成为获得FDA新药临床试验许可的第一种辐射防护药物等。下面对近年来辐射防护药研发取得的最新进展予以综述。
1 获得美国FDA新药临床试验授权的药物目前许多辐射防护药物正在研究或开发之中,而以下几种药物因为较好的抗辐射效果和安全性,已经获得美国FDA新药临床试验许可并处于临床试验阶段。
1.1 5-雄甾烯-3,17-二醇(androst-5-ene-3β,17β-diol,5-AED)/Neumune5-AED是获得FDA新药临床试验许可的第一种辐射防护药物[尤其是在治疗和预防急性放射综合征(acute radiation syndrome,ARS)方面]。研究表明,在全身致死剂量照射前或照射后单次注射5-AED均会提高小鼠存活率,不过照射前注射给药比照射后给药的辐射防护效果更显著[1-2];而且连续给药较单次注射5-AED可显著增加疗效、延长治疗时间及降低骨髓抑制[3];同时,在小鼠和灵长类动物(nonhuman primates,NHPs)模型上5-AED表现出辐射缓解作用[3];此外它还能够改善包括血小板水平在内的整体血液状况[4-6]。实验证实5-AED提高小鼠存活率与G-CSF相关;并且通过诱导调节细胞周期和凋亡的基因的表达,降低了辐射诱导的DNA损伤[7-8]。临床试验表明,5-AED的腹腔注射是一种安全有效的方式,可以刺激先天免疫和缓解ARS相关的嗜中性白细胞减少症和血小板减少症[9];也有课题组将5-AED制成纳米粒子在动物模型中取得了较好的辐射防护效果[10]。5-AED在有效的给药方式下对于治疗ARS效果显著,所以目前Hollis-Eden Pharmaceuticals(San Diego,CA,USA)正将其开发为辐射保护剂和缓解剂[4-6],但部分临床试验结果并没有公开发表。
1.2 金雀异黄酮(BIO 300)BIO 300又称4,5,7-三羟基异黄酮,是一种植物雌激素、抗氧化剂(自由基清除剂)以及蛋白酪氨酸激酶抑制剂(该抑制剂能够调节信号转导通路)。全身照射前给药,BIO 300能够降低小鼠的肺部损伤,刺激低水平造血细胞因子恢复正常[11-13];照射前的单次皮下给药或者肌内注射能够保护受照动物的造血系统[14-16]。过去BIO 300较低的生物利用度限制了口服给药的作用效果,但现在开发出的纳米制剂易于口服或者肌内注射,该制剂在小鼠模型上降低了辐射诱导的骨髓干细胞和祖细胞的凋亡和损伤[17]。由于对造血功能良好的保护作用和较佳的给药方式,FDA已经授权BIO 300作为治疗ARS的指定孤儿药并授予新药临床试验许可。目前Humanetics Pharmaceuticals(Minneapolis,MN,USA)正进行临床开发,一期临床试验结果表明BIO 300具有良好的安全性和耐受性[18-19]。
1.3 CBLB502(Entolimod)CBLB502是沙门杆菌鞭毛蛋白的衍生物,药理作用机制是通过结合靶细胞Toll样受体5(toll like receptor 5,TLR5)和激动k基因结合核因子信号通路,从而调节与抑制细胞凋亡、清除活性氧和系列细胞因子相关的基因表达[20]。Cleveland BioLabs公司(Buffalo,NY,USA)证实CBLB502为TLR5的配体,它能够改善鞭毛蛋白的辐射保护作用,同时减少毒性和致免疫原性[20-21]。致死剂量全身照射前24 h和照射后48 h单次注射CBLB502能够使小鼠避免患上胃肠综合征和造血亚综合征,并且显著改善了小鼠的存活状况[21-22]。在NHPs模型试验中证实了同样的辐射保护和缓解作用[23]。G-CSF和IL-6是CBLB502在体内发挥辐射防护和缓解作用的关键细胞因子,对急性照射的啮齿动物使用G-CSF或者IL-6中和抗体可以消除它的防护作用[19]。此外,CBLB502可以减轻由三硝基苯磺酸导致的黏膜损伤、抑制炎症反应与TLR表达[22, 24]。由于较好的防护作用和较低的毒性,FDA已授权CBLB502作为治疗ARS的指定孤儿药并授予新药临床试验许可,Cleveland BioLabs公司正通过临床实验将其开发为辐射防护药物,到目前为止的安全性评价表明它的耐受性良好。
1.4 HemaMaxHemaMax(重组人白介素-12,rHuIL-12)是一种异质二聚体细胞因子,在调节炎症反应与刺激自然杀伤细胞、巨噬细胞和T细胞产生γ干扰素方面具有重要作用[25-26]。全身照射前24 h或照射后1 h内单次剂量给药后,小鼠的特异性rHuIL-12会提高小鼠存活率[27-28]。在照射NHPs模型的实验中,HemaMax通过促进造血功能、免疫功能与胃肠功能的恢复而提高了存活率[29];此外,有课题组证明了在NHPs模型中rhuIL-12所具有的辐射缓解作用[30]。在小鼠放射复合损伤模型的局部给药实验中,HemaMax能够促进伤口的愈合,说明它能够用作复合损伤的缓解剂。由于较佳的辐射缓解作用,目前Neumedicines公司(Pasadena,CA,USA)正将rhuIL-12开发为辐射缓解剂。
1.5 ON01210ON01210(氯苄基砜衍生物)也作Ex-RAD(Recilisib),是一种新颖的小分子激酶抑制剂。与大多数辐射防护药物不同,Ex-RAD的作用机制不是清除自由基或阻滞细胞周期。现有研究表明,Ex-RAD作为辐射防护药物在DNA修复路径上有新的作用机制[31]。小鼠在照射前皮下或口服给药Ex-RAD后,对60Co γ射线所导致的损伤能提供重要的保护作用[32-33]。在给药后Ex-RAD能够快速缓解辐射诱导的各类血细胞减少症,修复骨髓功能[34];保护包括骨髓细胞和肠隐窝细胞避免辐射诱导的细胞凋亡[28],从而提高小鼠存活率。这些保护作用可能是由于Ex-RAD影响了相关的信号通路,例如,导致共济失调毛细血管扩张突变基因p53调节的DNA损伤应答减少,缓解辐射诱导的造血毒性;通过上调照射后细胞的磷脂酰肌醇-3激酶或蛋白激酶B通路产生保护作用等[31]。目前Ex-RAD正被Onconova Therapeutics公司 (Newtown,PA,USA)开发为辐射防护药物,但相关药理作用机制仍需要进一步深入研究。
2 临床前研究阶段药物 2.1 AEOL 10150AEOL 10150(meso-porphyrin mimetic)是由Aeolus Pharmaceuticals公司 (Mission Viejo,CA,USA)所开发的辐射防护药物。该药是一种作用新颖且耐受性良好的抗氧化剂,对于急性辐射损伤,特别是急性肺部辐射损伤具有显著地保护作用和缓解作用[35]。通过对小鼠和NHPs辐射损伤模型持续给药AEOL 10150的研究可以证明,AEOL 10150能够改善急性病理状况和提高存活率;有效地缓解致死性辐射诱导的肺部损伤,提高存活率[36-37]。该药将会捕获和中和电离辐射产生的活性氧和活性氮,减少氧化应激和炎性反应。该药的开发对于ARS,特别是肺部严重的辐射损伤具有重要意义。
2.2 ALXN4100TPO由Alexion制药公司(Cheshire,CT,USA)合成的ALXN4100TPO是一种促血小板生成素(thrombopoietin,TPO)受体激动剂,它能够减少内源性的TPO抗体生成。该合成激动剂在两种不同小鼠的辐射损伤模型上产生了刺激巨核细胞生成的作用,而且通过抑制骨髓损伤和血小板减少而有效地降低了辐射产生的致死性损伤[38-39]。相关实验表明当皮下注射给药ALXN4100TPO时能够刺激骨髓外造血,且没有致命的不良反应[40]。尽管ALXN4100TPO作为辐射防护药可以预防γ射线损伤,但是对于γ射线和中子射线混合损伤不能产生保护作用[41]。整体来看,ALXN4100TPO能够有效减少辐射后造血功能的损伤,Alexion制药公司正将其开发为辐射防护药。
2.3 PaliferminPalifermin是由角化细胞生长因子除去氨基末端生成,而角化细胞生长因子能够促进辐射损伤后黏膜的恢复[42]。Palifermin的保护作用是增殖刺激和抗凋亡作用相综合的结果[43]。临床前研究表明,Palifermin可以改善化疗和放疗的黏膜毒性[43];降低头颈部癌患者化疗时的口腔黏膜炎或接受其他化疗时患者的黏膜炎发病率,保护黏膜[44-45]。需要注意的是,Palifermin可以刺激造血系统移植后的免疫重构,也能够减少同种异体骨髓移植后的移植物抗宿主疾病[46]。所以,Palifermin是潜在的辐射黏膜损伤治疗药物。
2.4 磷脂酰肌醇-3激酶(phosphoinisitide-3 kinase,PI3K)抑制剂(LY294002)电离辐射会导致遗传毒性,触发自适应细胞反应,例如PI3K或蛋白激酶B信号级联放大的激活。细胞周期检查点是辐射后细胞存活的重要调节机制,因此研究γ射线照射后给药PI3K抑制剂导致的细胞周期变化具有重要意义[47]。在致死剂量γ射线照射后单剂量给药LY294002显著提高了小鼠存活率[47]。通过测定组蛋白H2AX发现,辐射后给药LY294002增加了G1和G2期细胞数量、减少了S期细胞和DNA损伤[47]。因此,照射后PI3K抑制剂的药理作用可以抑制细胞死亡,但开发为辐射防护药仍需要大量毒理实验和安全性、有效性研究。
2.5 成纤维细胞生长因子肽(fibroblast growth factor peptide,FGF-P)FGF-P在辐射诱导的造血综合征模型中缓解了败血症和出血症状,并抑制了胃肠道和皮肤综合征的恶化[48]。同时,FGF-P可以刺激辐射小鼠的骨髓细胞生长,白细胞、粒细胞、pro-B和pre-B细胞的数量也同时增加。而FGF-P几乎不诱导或不产生有害炎症或血管渗漏,并且与其他生长因子、血管生成因子和细胞因子相区别。虽然重组FGFs在几个正在进行的临床试验中已被证明是安全的,但它们合成昂贵、保质期有限。研究证实FGF-P是一种安全、有效、广谱的辐射缓解剂,并有望用于热灼伤、缺血性伤口愈合和干细胞再生[48]。所以FGF-P对于辐射损伤中造血综合征的治疗具有重要作用。
2.6 组蛋白脱乙酰酶抑制剂——苯丁酸组蛋白脱乙酰酶抑制剂可以抑制皮肤辐射综合征恶化和刺激造血功能[49-50]。苯丁酸是一种新的抗肿瘤药,在照射前给药可以抑制γ射线导致的辐射损伤,并且在小鼠模型的试验中剂量减低系数为1.31;当在辐照后给药情况下,其可以显著缓解辐射损伤[51]。辐射前给药苯丁酸可以减弱DNA损伤和抑制辐射诱导的凋亡,说明苯丁酸是一种潜在的辐射防护药物[49]。
2.7 Geldanamycin类似物17-dimethylamino-ethy-lamino-17-demethoxygeldanamycin (17-DMAG)17-DMAG的单剂量给药提高了照射小鼠的存活率[52]。用17-DMAG预处理的小鼠在照射后股骨骨髓发育不全的情况减少,CD34和CD44的表达恢复,并且观察到骨髓细胞的存活。17-DMAG还可升高血清G-CSF水平,降低血清酪氨酸激酶3配体水平和减少白细胞耗竭;改善小肠组织损伤,促进绒毛和肠腺包括干细胞的恢复;但如果在照射后给药,则无效。17-DMAG具有开发为辐射防护药的价值,但作用机制和相应不良反应仍需进一步研究。
3 总结和展望近年来,虽然辐射防护药的研发有了不小进步,但相比其他疾病药物的研发,辐射防护药发展仍较为缓慢且存在较多问题。主要原因可能在于以下两个方面:首先就药物研究本身而言,药物的安全性、有效性和稳定性等问题并没有得到很好的解决;其次,整个研究已经由热门主流阶段相对变冷,东欧剧变,苏联解体之后,人员和资金的投入大大减少,目前辐射防护药物开发的资金支持主要来源于政府。
然而知识产权保护和独家销售权吸引了以企业为导向的生物医学研究,并促进了药物开发领域的发展。具有较强研发实力的大型制药公司也开始对具有相对较小市场的药物开发感兴趣,从而在一定程度上促进了辐射防护药的发展。
目前,LY294002、Palifermin和17-DMAG等正处在早期研究开发阶段;5-AED和BIO 300虽然是效果相对较好的药物且最有希望应用于临床,但仍需要更丰富的临床试验数据证明其有效性和安全性。此外,本篇报道之外的Filgrastim(G-CSF)已被FDA作为超说明书用药用于治疗核事故辐射损伤,但亚致死性辐射照射后Filgrastim的有效性尚未确定,同时存在着一些不良反应如发热、肌痛、缺氧、Sweet综合征等等,因此Filgrastim的广泛临床应用还有待进一步的研究[53]。所以,从整体来看能够刺激造血、调节机体免疫功能、抗感染的小分子化学药物和生物药可能是未来重点研究和探索的方向;并且基于明确靶点的靶向性小分子药物的合理设计开发也是辐射防护药重要的探索方向。
利益冲突 本研究由署名作者按以下贡献声明独立开展,不涉及任何利益冲突。
作者贡献声明 张源和杨福军负责文献查阅和论文撰写;徐文清负责论文指导和审校。
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