李 敏，趙德華，王繼生*

·綜述·

抗輻射藥物研究進(jìn)展

李 敏1，趙德華2，王繼生1*

抗輻射藥物主要用于保護(hù)暴露電離輻射環(huán)境下的機體，同時不影響腫瘤細(xì)胞對放射治療的敏感性。按照來源分類主要包括天然抗輻射藥物與非天然抗輻射藥物；按照化學(xué)結(jié)構(gòu)分類主要包括維生素類、黃酮類、甲基黃嘌呤類、巰基類、氮氧自由基類、二苯并咪唑類、富勒烯及其他新型化合物。本文對不同來源與結(jié)構(gòu)的抗輻射藥物進(jìn)行綜述，以期為尋找更理想的抗輻射藥物提供參考依據(jù)。

輻射；抗輻射藥物；結(jié)構(gòu)

0 引言

電離輻射是一種主要由電磁波(X、γ射線)或粒子(α、β、中子)組成的能量，可通過各種途徑(微循環(huán)障礙、細(xì)胞凋亡、癌變、DNA突變等)對機體的造血功能[1]、消化系統(tǒng)[2-3]及免疫系統(tǒng)[4]造成顯著影響。其中，急性輻射綜合征[5](Acute radiation syndrome，ARS)是一種短時間內(nèi)高能量射線照射全身或局部而引起的疾病，其主要損傷部位為造血系統(tǒng)、胃腸道系統(tǒng)，可導(dǎo)致神經(jīng)壓迫綜合征，嚴(yán)重時可危及生命。為了降低電離輻射對人體造成的損傷，抗輻射藥物的開發(fā)和利用已成為輻射保護(hù)及損傷救治的研究熱點。而理想的抗輻射藥物應(yīng)該在保護(hù)正常細(xì)胞的同時，不影響腫瘤細(xì)胞對射線的敏感性[5-6]。為了解抗輻射藥物的研究現(xiàn)狀，本文對不同作用機制的抗輻射藥物進(jìn)行綜述，以期為抗輻射藥物的開發(fā)與應(yīng)用提供理論依據(jù)。

1 天然來源的抗輻射藥物

1.1 食物中的抗氧化劑 維生素A、維生素C、維生素E通過阻斷自由基引起的鏈?zhǔn)椒磻?yīng)而達(dá)到輻射防護(hù)的作用。Rostami等[7]通過體外微核試驗證實維生素C能夠降低6 mV的X射線輻照下人外周血淋巴細(xì)胞誘導(dǎo)產(chǎn)生的遺傳毒性。Mathew等[8]對抗壞血酸葡萄糖苷(Ascorbic acid monoglucoside，AsAG)進(jìn)行脈沖輻射分解試驗表明，AsAG通過清除自由基起到保護(hù)作用，25 Gy γ輻照前對小鼠使用AsAG能夠保護(hù)肝組織中脂質(zhì)過氧化，同時，對輻射后質(zhì)粒DNA進(jìn)行的瓊脂糖凝膠電泳試驗的結(jié)果表明，AsAG能夠保護(hù)質(zhì)粒pBR322 DNA免受γ輻射誘導(dǎo)鏈斷裂。Srinivasan等[9]研究表明，維生素E單獨使用或與WR-3689(氨基硫醇類化合物)聯(lián)用能增加輻照小鼠的生存率。Suman等[10]報道，γ-生育酚(Gamma tocotrienol，GT3)能夠上調(diào)抗凋亡基因表達(dá)，提高小腸細(xì)胞生存率，從而起到降低放射誘導(dǎo)的胃腸道毒性反應(yīng)。另一個抗氧化劑-硒元素，其輻射防護(hù)作用已經(jīng)在實驗室和臨床得到了證實[11-12]。Sieber等[13]發(fā)現(xiàn)，高劑量的硒膳食補充可減輕輻照大鼠的放射性腎損傷，進(jìn)一步研究發(fā)現(xiàn)，連續(xù)4個月補充200 μg/d 亞硒酸鈉或硒-L-蛋氨酸能夠大幅緩解輻射腎病，降低腦外傷的BUN水平(從115 mg/mL降至34 mg/mL)及組織病理學(xué)異常的發(fā)生率[14]。

1.2 褪黑素 褪黑素是松果腺分泌的激素，能夠有效清除羥基和過氧化物自由基[15]。Shirazi等[16]研究表明，褪黑素具有輻射防護(hù)的功能，可提高輻照大鼠的生存率，Koc等[17]提出，褪黑激素可以防止γ射線導(dǎo)致大鼠出現(xiàn)肝組織氧化損傷。Shirazi等[16]在放射前或放射后給予患者褪黑素，發(fā)現(xiàn)褪黑素可通過降低丙二醛水平和提高谷胱甘肽水平，來降低肝臟損傷的發(fā)生率及損傷程度。Fernández-Gil等[18]研究表明，褪黑素與降低炎癥反應(yīng)，抑制NF-κB信號通路的激活及 NLRP3炎性通路的活化有關(guān)，而口服褪黑素凝膠可降低放療患者發(fā)生胃腸綜合征的概率。此外，相關(guān)研究表明，無論是單獨使用褪黑素還是與其他藥物聯(lián)用，放療患者的臨床預(yù)后都會得到一定的提高[19-20]。

1.4 甲基黃嘌呤 甲基黃嘌呤包括己酮可可堿、咖啡因、可可堿和茶堿。Berbée等[27]研究表明，己酮可可堿單用或與γ-生育三烯酚聯(lián)合用藥可緩解患者造血系統(tǒng)損傷。George等[28]的臨床隨機對照試驗顯示，己酮可可堿和維生素E能預(yù)防高危乳腺癌患者放療后出現(xiàn)肺纖維化。Asadullina等[29]利用流式細(xì)胞微核試驗發(fā)現(xiàn)，肌苷-5′-磷酸能夠減少DNA損傷來起到輻射保護(hù)作用。另外的一項研究表明，在放射前或放射后給予咖啡因(80～100 mg/kg)可減少小鼠出現(xiàn)放射性皮膚損傷，且不影響腫瘤細(xì)胞對放射的敏感性[28]。

1.5 草本植物類的抗輻射藥物 植物來源的天然化合物具有毒性低、耐受性好的特點[30]，因此成為抗輻射藥物的研究熱點，相關(guān)研究表明，姜黃、烏梅、木蘋果(也稱印度桔橘)、薄荷、黃綠茶、紅茶多酚、銀杏提取物、葡萄提取物、大豆異黃酮、生姜等都具有一定的抗輻射作用[31-32]。Zbikowska等[33]研究發(fā)現(xiàn)，辣木根的多酚類化合物可防止γ射線輻照造成的光氧化損傷。Szejk等[34]研究表明，薔薇科和菊科植物的多酚提取物能減少輻射引起的脂質(zhì)過氧化反應(yīng)及DNA損傷。而Kim等[35]研究發(fā)現(xiàn)，100 mg/kg人參苷可通過對氧化應(yīng)激和細(xì)胞凋亡的調(diào)控來防止放射性肝損傷的發(fā)生。Ma等[36]研究顯示，阿魏酸可對抗輻射誘發(fā)的氧化應(yīng)激反應(yīng)。此外，另一項研究結(jié)果表明，川芎嗪可通過調(diào)控NF-κB通路來保護(hù)淋巴細(xì)胞免受輻射誘導(dǎo)的細(xì)胞凋亡[37]。

2 非天然來源的抗輻射藥物

2.1 巰基類化合物的抗輻射藥物 Patt等[38]首次報道半胱氨酸(含-SH)具有輻射防護(hù)作用，隨后，研究者們合成了一系列含氨基硫醇基團的化合物并證實了其具有較強的抗輻射活性。其中最成功的化合物是氨磷汀[39](WR-2721)，氨磷汀為前體藥物，在體內(nèi)通過去磷酸化轉(zhuǎn)化成活性形式WR-106來發(fā)揮藥理作用，并于1995年被美國FDA批準(zhǔn)用于放療保護(hù)和化療保護(hù)。Maisin等[40]報道，尼莫地平10 mg/kg聯(lián)合WR-151327(氨基硫醇類化合物)200 mg/kg的輻射保護(hù)作用要強于單用WR-151327。此外，采用肌肉組織氧分壓的電子順磁共振光譜和成像技術(shù)來測量組織中的血氧飽和度，結(jié)果發(fā)現(xiàn)，氨磷汀可以降低肌肉和腫瘤組織的氧分壓，表明氧分壓的降低可能有助于氨磷汀發(fā)揮輻射防護(hù)作用[41-42]。

PrC-210是氨基硫醇類似物，對全身致死劑量的射線輻照具有抗輻射活性[43]。體外研究表明，PrC-210可抑制人成纖維細(xì)胞的生長并能抑制p21蛋白的表達(dá)，p21蛋白主要調(diào)節(jié)細(xì)胞周期由G1期向S期轉(zhuǎn)化[44]。在動物模型試驗中，研究結(jié)果表明，在皮膚照射前腹腔或局部給予PrC-210可防止2～3級的放射性皮炎[43]。此外，Copp等[45]研究結(jié)果顯示，腹腔或口服給予輻照小鼠/大鼠PrC-210，輻照小鼠/大鼠的存活率為100%，且臨床相關(guān)劑量下的PrC-210并未出現(xiàn)惡心、嘔吐和低血壓等毒副反應(yīng)。盡管氨磷汀的劑量系數(shù)為1.6時，其惡心、嘔吐和低血壓的發(fā)生率為100%，但迄今為止，氨磷汀仍被視為最成功的抗輻射藥物并被FDA批準(zhǔn)用于放療患者。與之相比，PrC-210在劑量系數(shù)為1.6時未出現(xiàn)任何的毒副反應(yīng)。提示PrC-210具有開發(fā)成為新輻射防護(hù)劑的潛力和臨床應(yīng)用價值。

2.2 非巰基類化合物的輻射保護(hù)劑

2.2.1 氮氧自由基 氮氧自由基是由C、N、O、H原子組成的一種穩(wěn)定的自由基化合物，可通過與多種配體結(jié)合來為正常細(xì)胞提供輻射保護(hù)作用[46]，其主要作用機制為清除超氧化物陰離子，降低過渡金屬氧化性及抑制脂質(zhì)過氧化反應(yīng)。目前已有一系列的低分子量氮氧自由基得到合成，并且其抗輻射活性得到證實[47]，其中2個代表性的化合物分別為Tempol(4-羥基-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]研究發(fā)現(xiàn)，Tempol 在保護(hù)唾液腺的同時還不影響腫瘤細(xì)胞對射線的敏感性。最近，Davis等[49]發(fā)現(xiàn)了一種比Tempol具有更高效的輻射防護(hù)作用和血腦穿透作用的氮氧自由基化合物。

2.2.2 二苯并咪唑 二苯并咪唑雜環(huán)芳香族化合物是由2個咪唑基和1個酚基構(gòu)成，它通過作用于DNA來顯示出抗輻射活性[50]。研究表明，雙苯并咪唑衍生物Hoechst-33342(H-342)和Hoechst-33258可抑制輻照小鼠微核的形成，而靜脈注射80 mg/kg 的H-342可抑制細(xì)胞的凋亡反應(yīng)和防止早期輻射導(dǎo)致的內(nèi)皮細(xì)胞損傷[51]。Martin等[52]成功合成了methylproamine，一個新的Hoechst 33342類似物，其輻射防護(hù)作用大約是WR1065的100倍。Tawar等[47]利用動物模型證明了DMA和TBZ(新型毒副作用低的苯并咪唑衍生物)能引起核固縮，清除自由基，防止輻射導(dǎo)致的DNA損傷。進(jìn)一步研究表明，DMA可通過激活NF-κB/IKK通路而顯示出抗輻射活性[53]。

2.2.3 富勒烯 富勒烯是碳的同素異形體，由不同數(shù)目的碳原子組成。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]采用動物模型實驗研究表明，C60的富勒烯化合物DF-1比氨磷汀具有更顯著的輻射防護(hù)作用和更低的毒副反應(yīng)。另外，Daroczi等[57]進(jìn)行的斑馬魚模型試驗結(jié)果也表明DF-1具有較好的抗輻射活性。

2.2.4 超氧化物歧化酶-金屬配合物 超氧化物歧化酶(SOD)可與銅、鋅、錳結(jié)合，從而以金屬-SOD的形式存在，可通過加速氧自由基轉(zhuǎn)化為O2和H2O2來清除氧自由基[55]。Borrelli等[58]采用基因療法重組活性錳超氧化物歧化酶(Mn-SOD)進(jìn)行體內(nèi)試驗，發(fā)現(xiàn)其不僅對正常細(xì)胞具有輻射保護(hù)作用，并且能夠增強腫瘤細(xì)胞對射線的敏感性。雖然臨床前相關(guān)研究表明SOD可以作為一種有效的抗輻射藥物，但因其半衰期較短、分子量高而無法自由穿過細(xì)胞膜，從而導(dǎo)致其臨床應(yīng)用受到限制[59]。而Liu等[60]成功合成了肝素-SOD配合物，該配合物能顯著延長血漿中SOD的半衰期。另外一種SOD類似物M40403[61]也可保護(hù)小鼠免受致命輻射劑量的傷害。

2.2.5 HMG-CoA還原酶抑制劑 HMG-CoA還原酶抑制劑(他汀類藥物)是甲羥戊酸途徑的限速酶，是由膽固醇和其他類異戊二烯合成。Fritz等[62]研究發(fā)現(xiàn)，HMG-CoA還原酶抑制劑具有一定的抗輻射作用。Berbée等[63]研究發(fā)現(xiàn)，γ-生育三烯酸可防止輻照小鼠出現(xiàn)放射性腸炎，還可通過調(diào)節(jié)HMG-CoA還原酶來抑制血管的過氧化作用。Nübel等[64]采用原代人臍靜脈內(nèi)皮細(xì)胞分析洛伐他汀對IR引起的細(xì)胞毒性，發(fā)現(xiàn)洛伐他汀在濃度為1 μmol/L 時，對人血管內(nèi)皮細(xì)胞具有抗輻射和抗細(xì)胞凋亡的作用。

2.2.6 Toll受體5激動劑(CBLB502) CBLB502是從沙門氏菌鞭毛蛋白中提取并通過藥理優(yōu)化實驗篩選出的多肽類藥物，是一種Toll樣受體5激動劑，目前，各種體內(nèi)實驗均顯示其具有較好的輻射防護(hù)作用[6]。Burdelya等[65]研究發(fā)現(xiàn)，單劑量的CBLB502(0.2 mg/kg)可防止輻照小鼠(10、13 Gy)出現(xiàn)胃腸系統(tǒng)綜合征和造血系統(tǒng)綜合征，且并未影響腫瘤細(xì)胞對放射的敏感性。進(jìn)一步研究表明，CBLB502可通過激活NF-κB和STAT3κ信號轉(zhuǎn)導(dǎo)通路來保護(hù)輻照小鼠免受致死性的輻射傷害[65]。另外，Burdelya等[66]發(fā)現(xiàn)，CBLB502還可保護(hù)輻照小鼠出現(xiàn)由輻射引起的皮炎和口腔黏膜炎。同時，Wang等[67]研究表明，CBLB502可防止輻照小鼠出現(xiàn)放射性肺炎及肺纖維化。

2.2.7 其他新型抗輻射藥物 Singh等[68]研究表明，CBLB613(TLR2/6激動劑)對致死劑量的60Co γ射線具有輻射保護(hù)作用。而Johnson等[69]研究發(fā)現(xiàn)，選擇性CDK4/6抑制劑(PD033291)可減輕輻照小鼠的造血系統(tǒng)毒性，并能提高小鼠的存活率。Gluzman-Poltorak等[70]提出，重組人IL-12能降低輻射導(dǎo)致的造血系統(tǒng)毒性和感染，從而顯著提高獼猴的生存率。Ma等[71]研究表明，成纖維細(xì)胞生長因子肽可促進(jìn)體內(nèi)骨髓造血干細(xì)胞的恢復(fù)。也有報道，粒細(xì)胞和巨噬細(xì)胞的集落刺激因子具有抗輻射作用[72]。同時，Doan等[73]研究顯示，表皮生長因子可提高全身照射后造血系統(tǒng)的恢復(fù)能力。此外，有報道，格爾德霉素類似物(17-DMAG)可增加骨髓中CD34、CD44以及血清中性粒細(xì)胞集落刺激因子水平，上調(diào)Lgr5的表達(dá)，激活Lgr5腸隱窩干細(xì)胞，從而加速絨毛的修復(fù)和恢復(fù)[74]。目前，包括CBLB502、5-雄烯二醇、Recilisib/On01210、BIO300、Orbeshield、Hemamax、Neupogen在內(nèi)的7個抗輻射藥物已經(jīng)被FDA列為新藥研究項目[75]，具有良好的臨床應(yīng)用前景。

3 總結(jié)及展望

綜上所述，理想的抗輻射藥物需要具備以下3個特點：①選擇性強，即對正常細(xì)胞具有較強的輻射防護(hù)作用，而對腫瘤細(xì)胞的影響作用較弱；②毒副反應(yīng)低，患者可耐受，能在臨床廣泛使用；③易獲得，成本低。目前被FDA批準(zhǔn)用于放療防護(hù)的氨磷汀和帕利，雖然療效確切，但毒副反應(yīng)較大，患者難以耐受，因此，在臨床上難以被廣泛應(yīng)用，故需要尋找更加安全、有效且經(jīng)濟的抗輻射藥物來滿足臨床的需求。而天然與生物來源的藥物與傳統(tǒng)的化學(xué)合成藥物相比，具有抗輻射活性高、選擇性強、毒副反應(yīng)低的優(yōu)點，因此，可能會作為新型的抗輻射藥物而具有良好的臨床應(yīng)用前景。

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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.西南醫(yī)科大學(xué)藥學(xué)院，四川 瀘州 646000；2.綿陽市第三人民醫(yī)院，四川 綿陽 621000

四川省科技廳資助項目(2014JY0058)

*

10.14053/j.cnki.ppcr.201712023