人黑素瘤藥物研究進(jìn)展

付靖波， 于 斌， 張紅霞， 朱海英*

1. 海軍軍醫(yī)大學(xué)基礎(chǔ)部細(xì)胞生物學(xué)教研室，上海200433 2. 復(fù)旦大學(xué)生命科學(xué)院，上海200433

·綜述·

人黑素瘤藥物研究進(jìn)展

付靖波1， 于 斌2， 張紅霞1， 朱海英1*

1. 海軍軍醫(yī)大學(xué)基礎(chǔ)部細(xì)胞生物學(xué)教研室，上海200433 2. 復(fù)旦大學(xué)生命科學(xué)院，上海200433

黑素瘤患者死亡率較高。其治療方法除了傳統(tǒng)的手術(shù)切除和放射治療外，化療一度成為主要的治療手段。近年來，隨著人們對黑素瘤發(fā)生發(fā)展分子機(jī)制的深入研究，基于靶向治療、生物免疫治療的方法和藥物不斷涌現(xiàn)。目前，除了已經(jīng)在臨床治療中使用的藥物外，一些正在進(jìn)行臨床研究的待批準(zhǔn)藥物和正進(jìn)行基礎(chǔ)研究的潛在藥物也表現(xiàn)出良好的應(yīng)用前景。本文就目前治療黑素瘤的代表性藥物及潛在藥物的分子機(jī)制及治療效果作一綜述。

黑素瘤；多藥聯(lián)合治療；生物免疫治療；靶向治療

黑素瘤起源于皮膚、黏膜和色素膜的黑素細(xì)胞。雖然黑素瘤的發(fā)病率低于基底細(xì)胞癌和鱗狀細(xì)胞癌，但由于其易發(fā)生淋巴和血行轉(zhuǎn)移，且易轉(zhuǎn)移到肺、腦等器官，因此患者死亡率高。據(jù)統(tǒng)計(jì)，皮膚癌患者中僅4%的人罹患黑素瘤，但因皮膚癌死亡的患者中有80%為黑素瘤患者[1]。近年來，雖然多種腫瘤的發(fā)病增長率開始下降，但黑素瘤的發(fā)病增長率仍以每年3%增長[2]。廣泛切除聯(lián)合選擇性的淋巴清掃對于黑素瘤早期患者有較好的療效[3]；對于黑素瘤晚期患者，多采用放射性治療及化療，但這兩種方法對患者傷害較大而且療效欠佳、不良反應(yīng)大且患者易產(chǎn)生抗藥性。因此，需要尋找安全高效的黑素瘤治療方法。隨著人們對黑素瘤發(fā)病機(jī)制研究的深入，特別是相關(guān)突變基因的鑒定及關(guān)鍵免疫調(diào)節(jié)檢查點(diǎn)的發(fā)現(xiàn)，黑素瘤化療藥物治療、靶向治療、生物免疫治療及多藥物聯(lián)合治療手段得到不同程度的發(fā)展，本文就此作一綜述。

1 化療藥物

1975年，達(dá)卡巴嗪(dacarbazine, DITC)得到美國食品與藥物監(jiān)督管理局(FDA)批準(zhǔn)，成為第1個(gè)被用于黑素瘤臨床治療的化療藥物。此后，多種化療藥物先后出現(xiàn)，化療也一度成為黑素瘤臨床治療的主要手段，但各種化療藥物的治療效果參差不齊，相關(guān)藥物見表1。其中，替莫唑胺(temozolomide,TMZ)因有較好的穿透血腦屏障的能力而對治療腦轉(zhuǎn)移的黑素瘤顯示出更好的效果[4]；亞硝基脲類藥物可作用于處于不同增殖期的黑素瘤細(xì)胞。然而，化療不良反應(yīng)大、患者易產(chǎn)生抗藥性的缺陷使單一化療藥物難以成為黑素瘤治療的長遠(yuǎn)選擇[5]。而以紫杉醇及長春花堿為代表的天然類藥物及新發(fā)現(xiàn)的天然藥物(如Honokiol、Forsythiae Fructus及P-Hydroxycinnamaldehyde)在良好地抑制黑素瘤的同時(shí)具有更低的毒性[6-8]。近年來，天然藥物與納米技術(shù)結(jié)合也取得了較大成效，納米材料荷載的天然藥物在具有更好的細(xì)胞吸收與靶向性的同時(shí)，具有更低的毒性。已有研究[9]證明，順鉑蛋白納米顆粒對黑素瘤細(xì)胞B16有明顯的抑制效果，提示納米分子與鉑類化合物共同作用可用于治療黑素瘤。白蛋白結(jié)合型紫杉醇已顯示出較好的療效，且與紫杉醇單藥相比有更低的致過敏性[10]。研究[11]表明，缺氧誘導(dǎo)因子-1α(HIF-1α)在腫瘤組織中的積累可促進(jìn)黑素瘤的進(jìn)展，導(dǎo)致患者生存率降低，而抗壞血酸(AA)和磷酸抗壞血酸-2(A2P)等可用以調(diào)節(jié)HIF-1α的積累和活性。此外，甲基砜可以抑制HIF-1α及血管內(nèi)皮生長因子(VEGF)、促血管生成蛋白和轉(zhuǎn)鐵蛋白等促腫瘤轉(zhuǎn)移的調(diào)節(jié)因子的表達(dá)[12]。

表1 黑素瘤化療藥物的作用機(jī)制及療效

PFS(progression-free-survival)：無進(jìn)展生存期；ORR(objective response rate)：客觀緩解率；OS(overall survival)：總生存期；OR(odd ratio)：比值比；OSR(overall survival rate)：總存活率；DCR(disease control rate)：疾病控制率

2 生物治療

黑素瘤為免疫原性較強(qiáng)的腫瘤，但因其具有“掩藏”抗原的特性，故常顯示出免疫逃逸性質(zhì)。因此，通過激發(fā)機(jī)體的免疫系統(tǒng)以減少瘤體微環(huán)境中調(diào)節(jié)性T淋巴細(xì)胞數(shù)量、增加細(xì)胞毒性T淋巴細(xì)胞數(shù)量進(jìn)而增強(qiáng)局部抗腫瘤免疫力在較長一段時(shí)間內(nèi)是黑素瘤治療的研究熱點(diǎn)。1991年，特異細(xì)胞毒性T細(xì)胞識別的人類黑素瘤抗原被成功分離。近些年，T細(xì)胞活化模式日益清晰，隨著T細(xì)胞活化的“雙信號模式”的闡明、樹突狀細(xì)胞(DC)免疫生物學(xué)的進(jìn)展和人類白細(xì)胞抗原(HLA)基因測序的完成，黑素瘤的生物治療得到進(jìn)一步發(fā)展[19]，其主要包括基因治療、細(xì)胞因子治療、過繼免疫治療以及疫苗治療。

2.1 細(xì)胞因子治療 自IL-2作為治療晚期/轉(zhuǎn)移性黑素瘤的非特異性免疫調(diào)節(jié)劑而得到FDA批準(zhǔn)后，干擾素(INF)、貝伐單抗等因其對免疫系統(tǒng)的調(diào)節(jié)功能而多用于黑素瘤的免疫治療以及生物化學(xué)治療。其中，貝伐單抗更是常與免疫抑制劑及化療藥物聯(lián)合使用，且取得較好效果。而白細(xì)胞介素-2(IL-2)與IL-12除單藥使用外，在基因治療中也療效較好。研究[20]使用體內(nèi)電穿孔方法(EP)將IL-2與IL-12基因?qū)朕D(zhuǎn)移性黑素瘤細(xì)胞內(nèi)，在19例患者中，2例完全緩解。進(jìn)一步將IFN-γ與IL-2、IL-12在小鼠體內(nèi)聯(lián)用，CD8+的CTL細(xì)胞溶解酶活性增強(qiáng)[21]，這一結(jié)果為EP/IL-2、IL-12療法的進(jìn)一步發(fā)展提供了參考(表2)。

2.2 免疫檢查點(diǎn) 細(xì)胞因子治療可在短期內(nèi)增強(qiáng)體內(nèi)的免疫效應(yīng)，常效果不明顯且持續(xù)時(shí)間較短。隨著免疫檢查點(diǎn)的發(fā)現(xiàn)，特異性靶向免疫檢查點(diǎn)的單克隆抗體抑制了腫瘤免疫逃逸效應(yīng)，從而彌補(bǔ)了細(xì)胞因子治療的缺點(diǎn)(表3)。免疫檢查點(diǎn)參與T細(xì)胞的負(fù)調(diào)控，其在腫瘤患者的T細(xì)胞中表達(dá)相對升高，是造成腫瘤免疫逃逸現(xiàn)象的主要原因。目前已有兩大類免疫檢查點(diǎn)抑制劑被美國FDA批準(zhǔn)應(yīng)用于黑素瘤的臨床治療，分別為抗CTLA-4和抗PD-1/PD-L1的抗體。然而，腫瘤免疫檢查點(diǎn)抑制劑易產(chǎn)生較大的不良反應(yīng)，可在抑制腫瘤達(dá)到的同時(shí)殺傷正常細(xì)胞。

近年來新發(fā)現(xiàn)的免疫檢查點(diǎn)除CTLA-4和PD-1/L1外，還包括T細(xì)胞免疫球蛋白結(jié)構(gòu)域-3(TIM-3)、殺傷細(xì)胞抑制性受體(KIRs)、B7-H3等。目前以TIM-3的研究最為深入。其主要表達(dá)于輔助性T細(xì)胞(Th1)表面，與癌胚抗原相關(guān)細(xì)胞黏附分子1(CEACAM1)相互作用而誘發(fā)腫瘤免疫逃逸。在對轉(zhuǎn)移性的結(jié)腸癌細(xì)胞的TIM-3進(jìn)行敲除及對其功能進(jìn)行抑制后，調(diào)節(jié)性T細(xì)胞(Treg)與T細(xì)胞受到的抑制明顯減弱[27]，故TIM-3或可成為黑素瘤免疫治療的潛在靶點(diǎn)。

表2 黑素瘤細(xì)胞因子藥物的作用機(jī)制和療效

OS(overall survival)：總生存期；OSR(overall survival rate)：總存活率；RFS(recurrence-free survival)：無復(fù)發(fā)生存期

表3 免疫檢查點(diǎn)抑制劑的作用機(jī)制及治療效果

ORR(objective response rate)：客觀緩解率；OS(overall survival)：總生存期；OSR(overall survival rate)：總存活率；PFS(progression-free survival)：無進(jìn)展生存期

2.3 過繼性免疫治療(ACI) ACI中，腫瘤浸潤淋巴細(xì)胞(tumor-infiltrating lymphocytes,TIL)與嵌合抗原受體淋巴細(xì)胞(chimeric antigen receptor lymphocyte, CAR-T)因具有比腫瘤疫苗更為直接的抗瘤效果，成為近年來腫瘤免疫治療中的主力，在黑素瘤治療中的應(yīng)用也得到發(fā)展(表4)。TIL療法已在臨床試驗(yàn)中，而CAR-T療法也先后在體外及小鼠體內(nèi)證明了其有效性，曾被批準(zhǔn)進(jìn)行臨床試驗(yàn)，但治療效果因人、因病而異(表4)。雖然ACI在體表現(xiàn)出獨(dú)特的腫瘤治療效果，但易引起不良反應(yīng)(患者常伴有持續(xù)發(fā)熱)，患者治療后常反復(fù)發(fā)作，加之其在固體腫瘤中的療效弱于對血液瘤的療效，因此其在黑素瘤中的進(jìn)一步應(yīng)用受到阻礙。

表4 ACI的作用機(jī)制及治療效果

ORR(objective response rate)：客觀緩解率

3 靶向治療

黑素瘤的發(fā)展與細(xì)胞增殖、分化和細(xì)胞死亡的關(guān)鍵信號通路中分子的畸變有關(guān)。如表5所示，50%～60%的黑素瘤有RAS/RAF/MEK/ERK(MAPK)通路的改變，這使該途徑成為主要治療靶點(diǎn)。KIT的變異較不常見且主要發(fā)生在黏膜、肢端、皮膚以及MAPK抑制劑治療后的抗藥性黑素瘤中，約占黑素瘤總體突變種類的1%[40]。Buparlisib為PI3K-AKT通路的另一種抑制劑，最近有研究[41]表明，Buparlisib抑制PI3K-AKT通路在體內(nèi)與體外均起到對黑素瘤腦轉(zhuǎn)移的治療效果，提示PI3K-AKT通路可作為黑素瘤腦轉(zhuǎn)移的又一作用靶點(diǎn)。

細(xì)胞信號轉(zhuǎn)導(dǎo)系統(tǒng)極其復(fù)雜，且黑素瘤中各種細(xì)胞處于不同的生長階段。此外，轉(zhuǎn)移起始細(xì)胞的存在使黑素瘤治療后黑素瘤細(xì)胞仍會(huì)殘留甚至轉(zhuǎn)移。因此，針對某一單獨(dú)途徑的靶向治療的前期效果明顯，但治療后常有黑素瘤的復(fù)發(fā)，且復(fù)發(fā)的黑素瘤多對該藥物產(chǎn)生一定抗藥性。因此，在黑素瘤治療中，靶向藥物的使用應(yīng)當(dāng)同時(shí)針對黑素瘤細(xì)胞的多個(gè)代謝途徑，且應(yīng)與其他種類藥物聯(lián)合使用，以達(dá)到更徹底的治療效果。

此外，針對黑素瘤起始細(xì)胞的治療近年來也逐步得到重視。已有研究[50]表明，人ATP-結(jié)合盒(ABC)轉(zhuǎn)運(yùn)蛋白在黑素瘤的多重耐藥中起重要作用。相關(guān)蛋白ABCB5可被視為具有高致瘤能力的黑素瘤起始細(xì)胞的標(biāo)志物[51]，而解旋酶HAGE在ABCB5黑素瘤起始細(xì)胞介導(dǎo)的腫瘤發(fā)生中起關(guān)鍵作用[52]，故HAGE可作為特異性靶點(diǎn)用于針對黑素瘤起始細(xì)胞的靶向治療。

表5 靶向治療的作用機(jī)制及治療效果

PFS(progression-free survival)：無進(jìn)展生存期；OSR(overall survival rate)：總存活率；OIRR(overall intracranial response rate )：顱內(nèi)總體反應(yīng)率；ORR(objective response rate)：客觀緩解率；DCR(disease control rate)：疾病控制率；OS(overall survival)：總生存期

4 多藥聯(lián)合治療

多藥聯(lián)合治療主要包括多種同類藥物同時(shí)使用以及不同種類藥物聯(lián)合使用的治療(表6)。將化療藥物和生物制劑聯(lián)合應(yīng)用以同時(shí)對黑素瘤中的多個(gè)代謝途徑進(jìn)行抑制，比單藥治療有更高的客觀緩解率及更低的復(fù)發(fā)率。目前免疫檢查點(diǎn)抑制劑與其他藥物的聯(lián)合使用仍未得到充分發(fā)展。

表6 多藥物聯(lián)合的治療效果

RFS(recurrence-free survival)：無復(fù)發(fā)生存期；OS(overall survival)：總生存期；ORR(objective response rate)：客觀緩解率；PFS(progression-free survival)：無進(jìn)展生存期；OSR(overall survival rate)：總存活率

5 國內(nèi)黑素瘤治療藥物及研發(fā)

雖然黑素瘤在我國發(fā)病率較低，但是仍保持著較高的增長率，應(yīng)引起臨床工作者的重視。雖然近些年來我國在一些抗黑素瘤藥物如淋巴毒素-α衍生物[59]、納米氧化亞銅[60]、Aspartyl-chlorin p6 dimethylester(7b)[61]等的研發(fā)上取得了一定成效，但是我國對于黑素瘤的臨床藥物研究仍有所欠缺，尤其是抗黑素瘤藥物針對中國人的效果以及不良反應(yīng)的研究缺乏充足的數(shù)據(jù)支持[62](表7)。因此，針對中國人的黑素瘤藥物的臨床試驗(yàn)仍需進(jìn)一步開展。

表7 部分藥物在中國的臨床應(yīng)用效果

ORR(objective response rate)：客觀緩解率；DCR(disease control rate)：疾病控制率；RFS(recurrence-free survival)：無復(fù)發(fā)生存期

6 展 望

目前，隨著人們對黑素瘤生物學(xué)特性認(rèn)識的逐漸深入及新型生物材料的不斷涌現(xiàn)，在黑素瘤的治療方面，一些新型藥物和療法也展現(xiàn)出很好的發(fā)展前景。如納米材料因其低毒性、高靶向性、高效性以及易溶解性而對黑素瘤有較好的療效[60]。一些納米材料如納米氧化亞銅對黑素瘤治療的效果較好[64]。但是，納米材料在藥物荷載能力及保存方面明顯不足，加之缺乏完善的藥物毒理評價(jià)體系，導(dǎo)致納米類藥物在臨床的進(jìn)一步應(yīng)用受到阻礙[65]。而光敏劑在特定波長下產(chǎn)生的細(xì)胞毒性活性氧可引起腫瘤細(xì)胞的凋亡與壞死[66]。其中，卟吩姆鈉(porfimer sodium)為經(jīng)典的光敏劑，主要通過改變線粒體膜電位而誘導(dǎo)細(xì)胞凋亡，從而達(dá)到對黑素瘤的治療效果[67]；Aspartyl-chlorin p6 dimethylester (7b)為水溶性光敏劑，在小鼠體內(nèi)取得良好的黑素瘤抑制效果且具有低毒性[61]。此外，由于黑素瘤惡性程度、表型以及病情發(fā)展在年齡分布上有一定差異[68]，所以相關(guān)抗黑素瘤藥物研發(fā)應(yīng)當(dāng)針對不同年齡的患者群體進(jìn)行。

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Clinical treatment of human melanoma: recent progress

FU Jing-bo1, YU Bin2, ZHANG Hong-xia1, ZHU Hai-ying1*

1. Department of Cell Biology, College of Basic Medicine Sciences, Navy Military Medical University, Shanghai 200433, China 2. Department of Life Science, Fudan University, Shanghai 200433, China

The mortality rate of melanoma is high. Chemotherapy became the main treatment during the past years besides traditional surgical excision and radiotherapy.In recent years, with the in-depth study of the molecular mechanism of the occurrence and development of melanoma, new treatment methods and medicines basing on the target therapy and immune therapy have emerged constantly. At present, in addition to the drugs that have been used in clinical treatment, some of the drugs that are being approved for clinical research and the potential drugs which are still in basic research show good application prospects. In this paper, the molecular mechanism and therapeutic effect of the representative drugs or potential drugs in the treatment of melanoma were reviewed.

melanoma; multi-drug combination therapy; biological immunotherapy; targeted therapy

2017-03-17接受日期2017-06-08

國家自然科學(xué)基金(31471284). Supported by National Natural Science Foundation of China(31471284).

付靖波，海軍軍醫(yī)大學(xué)2015級臨床醫(yī)學(xué)專業(yè)本科學(xué)員. E-mail: fujingboi@163.com

*通信作者(Corresponding author). Tel: 021-81870944(0), E-mail: zinnia69@163.com

10.12025/j.issn.1008-6358.2017.20170223

R 739.5

A

[本文編輯] 廖曉瑜， 賈澤軍