修回日期: 2008-01-15
接受日期: 2008-01-23
在线出版日期: 2008-02-18
本文结合作者自己的研究成果, 对国内外近年来在应用光动力技术治疗消化系肿瘤方面的文献报道进行较全面的复习和综述, 介绍光动力治疗消化系肿瘤的技术方法及其机制. 应用光动力治疗消化系实体肿瘤具有较好的效果, 其与传统的手术、化疗、放疗、免疫治疗等方法并不矛盾, 他的主要机制是破坏肿瘤微血管、诱导肿瘤细胞凋亡、膜的损伤和引起免疫反应等.
引文著录: 葛海燕. 光动力治疗消化系肿瘤的进展与展望. 世界华人消化杂志 2008; 16(5): 457-462
Revised: January 15, 2008
Accepted: January 23, 2008
Published online: February 18, 2008
This paper reviews the photodynamic therapy for gastrointestinal tumors and its mechanisms, and describes the authors' experience with it. It is feasible and reasonable to use photodynamic therapy for gastrointestinal tumors. It is not in contradiction with PDT and traditional surgical treatment, chemotherapy, radiation and immune therapy, etc. The main mechanisms of photodynamic therapy for gastrointestinal tumors are to damage tumor microvasculature, induce cancer cell apoptosis, injure cancer cell membrane, and trigger immune reactions.
- Citation: Ge HY. Advances in photodynamic therapy for gastrointestinal tumors and its propect. Shijie Huaren Xiaohua Zazhi 2008; 16(5): 457-462
- URL: https://www.wjgnet.com/1009-3079/full/v16/i5/457.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v16.i5.457
光动力疗法(photodynamic therapy, PDT)是利用光敏剂对激光照射后产生的光化学反应来诊断或治疗肿瘤的新技术, 经过20多年来的发展, 其技术已经日趋成熟[1-2]. 国内外大量的实验研究和临床观察证明, PDT对血管瘤、息肉、不典型增生、良性肿瘤以及恶性肿瘤都有一定的作用[3-4]. 本文就近年来应用PDT治疗消化系肿瘤、PDT治疗肿瘤的机制研究所取得的成果、存在的问题以及解决这些问题的可能途径作简要介绍.
光动力治疗后可造成微血管内皮完整性的破坏, 内皮细胞损伤后胶原裸露促使血小板黏附于胶原纤维, 形成血小板黏集堆和微血栓; 血管内皮损伤后导致炎性因子释放, 引起血管收缩, 导致血细胞滞留凝集、血流停滞, 血管内的静水压增高, 富含蛋白质的液体从血管内到血管外, 水分流入组织间隙造成组织水肿、血容量降低; 血管血栓形成及血容量降低均能造成肿瘤组织缺血、缺氧、从而杀伤肿瘤组织[5-8].
光动力治疗引发的细胞凋亡, 一些研究表明, 光敏剂酞箐(phtalocyanine)光动力治疗引起线粒体的损伤, 细胞色素C从线粒体快速释放到细胞溶胶中诱导细胞凋亡, PDT引发凋亡反应的典型特征是细胞色素C的迅速释放, 半胱天冬酶(caspases)活化和凋亡小体形成[7,9-12]. 禹丽娜et al[13]在利用人淋巴肿瘤细胞系(Jurkat cell)进行的PDT实验中观察到, 照射30-60 min后细胞色素C释放, caspase23活化和多聚(ADP2核糖)聚合酶裂解. Mikes et al[14]运用caspase抑制剂发现, caspase23就足以发动PDT引起的凋亡发生.
PDT可引起照射组织内TNF、IL-1B、IL-2增加, 其原理可能是巨噬细胞发生吞噬反应[7,15]在结肠癌细胞系HT29的体外和体内模型中, PDT均能引起线粒体中HSP60的转录和翻译[16]. Abdel-Hady et al[17]报道PDT治疗肿瘤时可以激活补体系统. Korbelik et al长期致力于研究补体在PDT诱发抗肿瘤免疫反应中的作用, 认为补体激活是PDT诱发抗肿瘤免疫反应的一个重要过程, 光动力学疗法诱导的补体级联反应的活化和受照射肿瘤局部补体蛋白的沉积过程, 对PDT的抗肿瘤效果有很大影响, 而且补体激活剂和PDT的联合应用能够扩大PDT诱导的补体激活效应, 提高PDT的抗肿瘤效果[18-21].
近年来, 部分研究者深入研究了PDT对细胞膜性结构的影响, 光敏剂最初接触的部位是细胞膜或细胞内膜[22-24]. 膜敏化后细胞膜电位下降, 通过细胞膜的分子转运受到抑制, 细胞膜相关的酶被激活[17]. 光敏剂在激光作用下发生光化学反应[25], 使线粒体膜的通透性增加, 膜电位(ΔΨm)消失, 许多与诱导细胞凋亡相关的蛋白质因子释放于胞质中, 这些因子包括细胞色素C、凋亡诱导因子(apoptosis-inducing factor, AIF)、SMAC(second mitochondria 2 derived activator of caspases)等. 细胞色素C进入胞质, 与胞质中的dATP、凋亡活化因子21(APAF21)及原caspase29结合成复合物, 启动了caspase的级联活化, 最终使许多蛋白质因子活化, 如DNA裂解因子(DNA fragmentationfactor, DFF)、多聚腺苷聚合酶[Poly (ADP2ribose) polymerase, PARP], DNA依赖蛋白激酶(DNA2PKcs)、caspase激活的脱氧核糖酸酶抑制剂(inhibitor of caspase activated DNase, ICAD)等, 引起细胞凋亡特征的产生, 如细胞收缩、染色质凝聚并边缘化、DNA断裂、凋亡小体形成等[26]. PDT导致线粒体功能受损, 产生ATP减少, 进而引起线粒体内膜跨膜电位下降, 活性氧产生, 胞内pH值和Ca离子等改变[27], 从而启动细胞凋亡程序[17]. 内质网也是PDT作用的重要靶点. 光敏剂Foscan孵育MCF-7肿瘤细胞时, 内质网和高尔基复合体是光敏剂优先集中的位置, 并且通过激光照射, 他们也是被破坏的位置[26,28]. 许多光敏剂定位于溶酶体[29], 光照射后经过两种不同的途径引起细胞的死亡, 一种是通过溶酶体的酶释放到细胞质引起细胞的死亡, 另一种经过光照射后光敏剂重新定位于其他非溶酶体的靶点, 引起细胞的死亡[26].
癌前病变在胃肠道恶性肿瘤的发生、发展中具有重要地位[30], 结、直肠的腺瘤、息肉(尤其是家族性息肉病患者)、血吸虫病肉芽肿等癌前病变都与结、直肠癌的发生有密切关系[31-33]. 对于胃肠道癌前病变的处理, 以往都采用手术切除的方法进行治疗, 病灶虽小, 但是手术和手术引起的创伤往往很大. 随着微创医学理念的发展, 采用微创技术来治疗癌前病变, 引起研究者的兴趣. 从不同研究者的研究结果看, 光动力治疗的效果不尽一致, 同时对利用光动力治疗的患者必须密切随访, 以便及时发现和处理光动力治疗失败者. Smolka et al[34]报道应用氨基酮戊酸作为光敏剂[35-36], 并通过内镜系统将光导纤维引导到病灶部位, 对食道、胃和肠道的癌前病变进行PDT治疗, 发现每个患者对治疗都产生反应, 其中2例患者的病灶完全消退, 其他5例患者的病变缩小面积也达到60%以上, 表明ALA-PDT对胃肠道癌前病变可能是一种有效的治疗方法[37-38]. Weiss et al[39]对17例患者Barrett's食道并且高度间变或早期食道癌的患者进行光动力治疗, 并在治疗后的第3、6、9、12月进行随访, 满一年后则每6 mo一次. 其结果9例(占60%)患者高度间变或早期食道癌得到完全消除, 2例早期癌患者无反应, 1例高度间变患者的间变程度下降, 另1例无变化, 有4例患者则病情继续发展. 研究者认为光动力治疗食道癌前病变的有效率为60%, 不能奏效者40%, 因此, 在PDT治疗后需要密切随访.
2.2.1 食道癌: Eickhoff et al[40]应用5-氨基酮戊酸对长达10 cm的上段食道癌进行光动力治疗(5-ALA-PDT), 在3个疗程后, 利用内镜直视和超声内镜检查, 发现肿瘤已经完全消退, 并且组织活检也证实肿瘤已经完全消除. 该例患者经过23 mo的随访, 仍然没有复发征象, 因此认为早期表浅的食道鳞癌可以通过5-ALA-PDT完全治愈, 但是仍需对这些患者进行远期随访. 其他许多研究者的大量临床研究表明, PDT对食道癌确实具有治疗作用[41-48].
2.2.2 胃癌: 根治性切除是胃癌的首选治疗措施, 而且疗效十分肯定. 近几年来, 一些研究者对部分早期胃癌患者尝试应用PDT治疗, 目的是在治愈胃癌的同时, 使患者免除巨大的手术创伤[49-51]. Nakamura et al[52]用PDT治疗7例早期胃癌, 均获得成功, 术后病理活检未发现癌组织残留. Gahlen et al[53]认为, PDT对胃肠道早期小癌变、癌前病变是可行的, 对于拒绝手术治疗的胃肠道肿瘤患者, PDT可以用作替代治疗措施之一.
2.2.3 胆管癌: 胆管癌的发病率近年来一直呈增高趋势, 尤其是高位胆管癌的切除率仍然偏低, 远期生存时间并没有显著提高. 最近, Mayo Clinic Rochester的Prasad et al[54]采用光动力技术治疗25例已经无法手术切除的胆管癌患者, 其中BismuthⅠ型3例, Ⅲ型13例, Ⅳ型9例. 在注射光敏剂后48 h, 光纤经逆行插管(20例)或经皮肤穿刺(5例)引导到胆管癌部位, 进行激光照射. 所有患者每3 mo进行一次PDT治疗, 在PDT治疗后, 放置10-11.5 F胆管支架进行胆道减压. 患者总的平均生存期为344 d, 其中PDT治疗后的生存期为214 d, 1年生存率为30%. 多因素分析表明, 如果在影像学上存在明显肿块、确诊胆管癌和开始PDT治疗的时间间隔越长, 愈后就越差; 血清白蛋白水平越高, 预示PDT治疗后的死亡率就越低.
2.2.4 胰腺癌: Bown et al[55]对16例无法切除的胰腺癌患者进行光动力疗法的观察. 所有患者都有梗阻性黄疸, 事先通过放置胆道支架进行减黄处理. 注射光敏剂后3 d, 在CT引导下经皮胰腺穿刺将光线导引到肿瘤部位, 然后实施PDT. 其结果, 所有患者都有肿瘤坏死的征象, 14例在10 d内就出院, 2例由于肿瘤侵犯胃十二指肠动脉而发生大出血, 未经手术治疗就将出血控制. 在随访过程中, 3例出现十二指肠梗阻, 没有发生与PDT相关的死亡. 光动力治疗后的平均生存期是9.5 mo, 7例患者(44%)1年后健在.
2.2.5 转移癌: 对于胃肠道恶性肿瘤的腹腔内转移癌或肝转移癌, 目前仍然是临床治疗中的难点问题. 大多数患者已经无法根治性切除, 甚至已经失去手术时机, 而且化疗、放疗、免疫治疗等综合治疗措施也大多难以取得满意的疗效. 由于光动力治疗不会影响其他治疗方法的效果, 并且即使别的方法失败后, 光动力疗法仍然能够发挥效能, 近年来许多研究者积极探索利用光动力来治疗腹腔内广泛转移癌或肝转移癌, 取得了一些令人满意的初步疗效[56-58].
Hahn et al[3]对腹腔内转移性肿瘤和肉瘤的光动力治疗效果进行了二期临床试验, 他们分别对33例卵巢癌、37例胃肠道癌和30例肉瘤患者进行了观察, 其结果对腹腔内肿瘤进行光动力治疗是可行的, 但是并没有取得显著的完全缓解或长期控制的效果. 光敏剂摄取和肿瘤内氧化(tumor oxygenation)的不均一性(heterogeneity)、肿瘤对光敏剂摄取缺乏特异性以及组织内光学特性的不均一性是导致治疗效果不佳的主要原因[59-61].
Van Duijnhoven et al[62]对24例结直肠癌伴肝转移的31例无法手术切除的转移癌灶进行光动力治疗, 采用的光敏剂为5、10、15、20-羟苯菌绿素(mTHPBC), 分别在静脉注射光敏剂后12、48 h经皮穿刺插入光纤进行激光照射(60 J/cm2). 在PDT治疗后1 mo时检查发现, 所有患者的转移癌组织均发生坏死. 在副作用方面, 8例有轻微疼痛, 21例出现短暂的亚临床肝损害, 各有1例发生皮肤或胰腺损伤. 研究者认为对手术无法切除的肝转移病灶, 采用间质性mTHPBC光动力治疗, 是一种安全有效的方法[63].
进入21世纪以来, 随着PDT在国内的广泛开展, PDT的不足和局限性逐渐被人们认识, 加上最初时人们对PDT的期望值过高, 而在实际应用过程中, 一些患者PDT的疗效不尽满意. 除了PDT产生的皮肤光敏反应外, 光动力治疗中面临的问题还有: 由于可见光在组织中穿透性的限制, PDT对位于体内深部肿瘤的作用很微弱; 根据国家药事管理的法规, 当前国内还没有合格的光敏剂可供临床使用.
为了解决光线在实质性组织内的穿透问题, 目前主要采用在超声或CT引导下组织内穿刺的方法, 直接将光纤插入到深部肿瘤内和肿瘤组织周围. 在应用PDT治疗肝癌、胰腺癌等实质性肿瘤的过程中, 文献报道中普遍采用在超声或CT引导下经皮穿刺的PDT技术. 超声动力学治疗(sonodynamic therapy)是近年来新兴的一种技术, 他通过超声来激发声敏药物(sonosensitizer), 从而产生单线态氧等自由基, 启动脂质膜的过氧化反应, 进而杀伤肿瘤细胞. 超声动力学治疗的最大优点是可以穿透到深部组织.
由于光敏剂在体内循环需时较长, 在循环过程中受到吞噬细胞的破坏, 目前许多研究人员利用光敏剂激活剂缩短光敏剂到达靶器官或靶组织的途径及时间. Svensson et al的研究表明, 氢氧化氯苯是一种最潜在性的光敏素激活剂, 能够促使光敏素迅速进入肿瘤细胞内, 并且能迅速达到生物分布并从血液中清除[64].
光敏剂也可以用于光化学基因转染(photo chemicalgene transfection, PCGT). PCGT是一种新的基因转染技术, 他通过光化学反应, 导致内吞泡膜损伤, 释放泡内转染基因. 肖卫东et al[65]报道, 以阳离子聚合物距乙烯基亚胺(polyetheneimine, PET)为DNA载体, 增强绿光反应蛋白(enhanced green fluorescent protein, EGFP)质粒为目的DNA, 通过流式细胞计数对比观察光化学作用对阳离子聚合物介导EGFP质粒转染结肠癌细胞的影响. 结果显示, 光敏剂中介四-(对苯基磺酸)-卟吩钠(meso-tetraphenylporphine with two sulfonate groups on adjacent phenyl rings, TPPS2a)的胞内分布与内吞密切相关; 基于TPPS2a的光化学细胞毒性作用呈剂量依赖性; 与单纯质粒转染组和阳离子聚合物转染组相比, 光化学可明显提高阳离子聚合物介导转染目的DNA的阳性细胞率.
近年来, 国内外许多研究者利用光动力疗法(PDT)治疗消化系息肉、癌前病变和癌症等, 为肿瘤治疗增添了新的技术手段.
施瑞华, 教授, 南京医科大学第一附属医院消化内科
本文围绕如何将激光有效地导入到机体深部组织, PDT是否能够杀灭肿瘤细胞, PDT对实体性肿瘤的效果究竟如何评价以及其是通过什么机制导致肿瘤细胞凋亡和坏死等基础和临床研究中的热点、重点, 以及亟待研究的问题, 进行文献复习和述评.
对于脏腔表面的息肉、癌前病变和早期癌, PDT具有比较确切的疗效, 而对腹腔内的中晚期癌症, 通过B超、CT引导下的经皮穿刺技术, 也可将光导纤维插入到肿瘤部位, 从而产生光动力效应.
本文通过探讨PDT治疗过程中存在的问题和解决途径, 对进一步研究克服PDT的缺陷, 提高PDT疗效的技术方法有一定意义.
光动力疗法(PDT): 是指光敏剂在有氧环境中, 并且在激光照射下产生单线态氧等超氧离子, 进而导致受照射的肿瘤细胞凋亡、坏死的治疗方法.
本文写作规范, 层次清楚, 论据充分, 有一定的临床指导价值.
编辑: 程剑侠 电编: 何基才
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