抗輻射藥物研究進(jìn)展

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(jī)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(jī)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(jī)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(jī)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(tuán)的化合物并證實了其具有較強(qiáng)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(qiáng)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(jī)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(qiáng)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(qiáng)，即對正常細(xì)胞具有較強(qiáng)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(jì)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(qiáng)、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