5-ALA-光动力治疗鼻咽癌的实验研究
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摘要
鼻咽癌(nasopharyngeal carcinoma,NPC)是我国常见的恶性肿瘤之一,尤其以广东、广西最为多见,发病率可高达30/10万。由于早期鼻咽癌症状不明显导致患者就诊时往往已到中晚期,而目前以放、化疗为主的治疗方法只能使5年生存率达到50%～70%左右,且众多的放疗后并发症又严重影响着患者的生存质量,目前临床上对鼻咽癌的治疗已达瓶颈期,迫切需要一种新型有效的治疗方式来弥补放、化疗的不足。光动力学治疗(photodynamictherapy,PDT)自20世纪80年代初兴起以来,由于其选择性好,毒性小,起效快,可重复和与其他传统疗法协同作用等优点越来越受到人们的重视,随着新型光敏剂的发现,激光器的完善及临床经验的积累,PDT已成为肿瘤治疗的又一种新选择。
5—氨基酮戊酸(5-aminolevulinic acid,5-ALA)作为具有较强光敏作用的原卟啉Ⅸ生物合成前体,5-ALA及其某些酯类近几年被用于光动力治疗,5-ALA本身不是光敏剂,是光敏剂原卟啉的生物合成前体。本课题欲从体外、体内多个方面探讨5-ALA-PDT在鼻咽癌治疗中应用的可能性。
第一部分5-ALA对体外培养人鼻咽癌细胞CNE2系的光灭活作用
目的:探索5-ALA介导的光动力治疗在体外环境中对鼻咽癌细胞的光灭活作用,及5-ALA在细胞内代谢合成PpⅨ的规律、5-ALA暗毒性、5-ALA-PDT最适作用时间、最适作用剂量等。
方法:
1荧光分光光度法测定5-ALA在肿瘤细胞中合成原卟啉的情况;
2荧光倒置相差显微镜观察CNE2细胞吸收后5-ALA合成PpⅨ在细胞内的定位;
3 MTT细胞毒实验检测5-ALA对细胞的暗毒性、单纯辐照对细胞的影响、照光剂量对PDT的影响、不同5-ALA孵育时间的影响、血清对5-ALA-PDT的影响;
4流式细胞术检测5-ALA-PDT对肿瘤细胞的杀伤作用;
5光镜、透射电镜下观察5-ALA-PDT后细胞形态学的改变。
结果:
1.荧光分光光度法检测发射荧光强度观察PpⅨ的生成量:409nm的蓝紫光能激发细胞内合成的PpⅨ发射出635nm波长的红光,结果显示:产生的PpⅨ只存在于细胞中;2mmol/L5-ALA体外孵育浓度已达饱和;5-ALA吸收后在细胞内产生的PpⅨ量随时间的延长而逐渐增加,10小时前PpⅨ随时间增长得最快。
2.荧光倒置相差显微镜观察:5-ALA被CNE2细胞吸收后产生的PpⅨ主要存在于细胞膜和胞浆中。
3.MTT细胞毒实验:单纯5-ALA孵育及单纯冷光源激光辐照对肿瘤细胞的生长在10小时内几乎无影响(p＞0.1);5-ALA孵育浓度和时间一定时,1、2、5、8J辐照剂量的抑制率分别是:1J 34.3±4.6;2J 55.0±3.2;5J 92.0±6.2:8J 85.5±10.9;在光照剂量和强度一定的情况下,延长5-ALA药物的孵育时间可以明显提高PDT效应,但8小时为最长孵育时间,再延长时间对PDT影响不大;动物血清对5-ALA-PDT效应存在着明显的抑制作用,这种抑制作用可以通过增加5-ALA浓度,提高辐照剂量等而得到进一步增强。
4.流式细胞术检测不同浓度5-ALA和辐照剂量及血清存在下诱导的细胞凋亡率:2mmol/L 1J 62.3%;2mmol/L 2J 74.5%;2mmol/L 10%FBS2J 11.1%:4mmol/L 10%FBS 2J 28.8%;6mmol/L 10%FBS 2J 75.5%。
5.光镜下观察5-ALA-PDT后细胞形态学改变快,数分钟内即可在普通倒置相差显微镜下观察到细胞变圆、变小,细胞内大量的空泡形成、核膜着色加深,8小时后细胞分解成细颗粒状,部分细胞结构尚存。透射电镜下细胞染色质边集凝聚、断裂、核膜出泡及凋亡小体形成,胞浆内线粒体肿胀脱颗粒等。
结论:
1.5-ALA在细胞内合成的PpⅨ主要存在于细胞胞浆及包膜中,2mmol/L为体外最适浓度;
2.单用5-ALA孵育对细胞无毒性;单独辐照对细胞生长无影响;体外适量增大照光剂量可增强PDT对细胞的灭活作用,光剂量5J时达峰值;在5-ALA孵育浓度一致和照光剂量相等的情况下,延长ALA孵育时间可以增强PDT损伤效应;血清对5-ALA-PDT有明显的竞争性抑制作用;
3.诱导细胞凋亡为5-ALA-PDT杀伤细胞的主要作用机制,但当药物剂量过高、光剂量太大时,则诱导细胞坏死。
第二部分5-ALA对裸鼠人鼻咽癌移植瘤的光动力疗效
目的:建立裸鼠人鼻咽癌CNE2荷瘤模型,摸索5-ALA在体内的代谢情况,研究局部和腹腔给药方式下,5-ALA-PDT对肿瘤生长的抑制作用。
方法:
1.体外培养人鼻咽癌CNE2细胞,以2～5×10~6/0.2ml接种于裸鼠右腋下。
2.荧光分光光度法检测5-ALA在荷瘤小鼠体内各脏器、组织中合成PpⅨ的情况。
3.接种人鼻咽癌CNE2细胞,当肿瘤大小达0.1-0.15cm~3时随机分成4组,A、D组局部给予20%5-ALA100mg.kg~(-1),B组腹腔给予20%5-ALA100mg.kg~(-1),C组为对照组。3～3.5小时后A、B、D接受100mw.100J~(-1)630nm激光照射,24h后D组断颈处死;A、B、C组PDT处理后1、3、7、10、14d用游标卡尺测量肿瘤大小,14d断颈处死,称量3组瘤重。
4.取4组肿瘤组织制蜡块做病理切片、电镜检查等。
结果:
1.人鼻咽癌CNE2细胞接种成功率达100%,8～10天肿瘤大小可达0.1-0.15cm~3。
2.5-ALA吸收后主要在于肿瘤组织和肝脏中积聚合成PpⅨ,且肝脏组织中的含量高于肿瘤组织。PpⅨ在肝脏内一小时即达高峰,后逐渐下降,5小时与肿瘤组织含量基本一致;而肿瘤组织中的PpⅨ一小时起即可检测到,后逐渐升高,3～4小时左右达峰值,后逐渐下降,瘤旁粘膜、肌肉组织及肺、肾可少量吸收光敏剂而产生PpⅨ,而心脏几乎不含PpⅨ,正常组织除肝脏外与肿瘤组织的吸收比约为1:2～4。
3.5-ALA-PDT对小鼠无明显毒副反应,治疗后1天起治疗组与对照肿瘤体积就有明显的差异,14天后A、B、C3组肿瘤重量(g)分别是1.353±0.204、2.105±0.255、3.124±0.380,P=0.000;
4.透射电镜观察5-ALA-POT治疗后,细胞体积明显缩小,胞浆内出现大量空泡,为肿胀的线粒体,线粒体嵴短小而显示不清,核内染色质凝集、致密,呈颗粒、块状均质分布在核膜内侧,电子密度高,核中心染色质消失淡染,少数核膜出泡形成凋亡小体,存在与其他细胞周围或被吞噬,呈现典型的凋亡表现。部分边集的染色质断裂,到逐渐溶解消失。同时也存在部分坏死细胞,表现为细胞明显变性、解离、胞质疏松、膨胀,细胞膜破坏,线粒体脱颗粒、消失。病理切片显示PDT治疗后一天,局部血管扩张及弥漫性出血,细胞胞浆内出现大量空泡和多处灶状坏死及凋亡,。PDT治疗后14天,镜下见大片凝固性坏死,细胞核固缩,甚至只残留核形,而无嗜苏木素着色。
结论:
1.小鼠人鼻咽癌荷瘤模型建立成功;
2.5-ALA体内吸收后合成的PpⅨ主要分布于肝脏和肿瘤中,PpⅨ在肝脏中1小时内达峰值,在肿瘤中3小时左右达峰值;
3.5-ALA-PDT是安全可靠的治疗方法,能明显抑制人鼻咽癌肿瘤的生长,且局部治疗组明显优于全身治疗组;
4.透射电镜和病理切片证实5-ALA-PDT诱导肿瘤细胞凋亡和坏死。
第三部分5-ALA-PDT后血管生成、增殖能力及凋亡途径的探讨
目的:探讨5-ALA-PDT后血管生成、增殖能力及凋亡途径上的改变
方法:
1.实时荧光定量PCR检测血管内皮生长因子(vascular endothelial growthfactor,VEGF)、增殖细胞核抗原(proliferation cell nuclear antigen,PCNA)、半胱氨酸.天冬氨酸蛋白激酶-3、-8、-9(Caspase3、Caspase8、Caspase9)等基因mRNA水平的改变
2.免疫组化检测VEGFA、PCNA的蛋白表达水平及在细胞中的定位
3.Western-blot免疫印记法检测VEGFA、PCNA、Caspase9蛋白表达水平的差异及激酶激活状态的差异
结果:
1.在mRNA检测水平上治疗组1d及14d PCNA、Caspase9均高于对照组;
2.免疫组化检测显示VEGFA在治疗后急性期(1d)及全身给药组略高于对照组,而局部给药组略低于对照组,暂无明显统计学差异。PCNA在PDT后1d由于肿瘤细胞的代谢异常,胞核中的PCNA表达下调,核膜周边着色,PDT后14d存活的肿瘤细胞PCNA略高于对照组,p=0.386,暂无明显统计学差异。
3.Westem-blotting检测:局部治疗组14dVEGFA蛋白表达明显下调(p=0.000),PDT后1d组略上调;PCNA总蛋白含量无明显差异;Caspase9的原型减少,激活形式明显增多(p=0.015)。
结论:
1.VEGFA在mRNA水平无明显统计学差异,蛋白表达水平局部治疗组PDT后14天明显下调,而PDT后1天略为上调;
2.PCNA在mRNA水平治疗组1d及14d均明显高于对照组,有统计学差异;总蛋白水平无明显差异,但PDT后1天分布在胞核中的PCNA减少,提示功能上存在差异。
3.Caspase9在mRNA水平治疗组均高于对照组;蛋白水平原型的Caspase9减少,而激活形式增多。
Nasopharyngeal carcinoma(NPC)is very common in southeast of China,especially in Guangdong and Guangxi province,with a incidence up to 30/10~5.Most of the NPC patients are diagnosed in middle and advanced stage because of its early atypical symptoms,and the 5-yearl-survival rate is only 50%～70%after radiotherapy and chemotherapy,with severe complications. Thus other new method should be taken to improve the survival rate with less severe complications.Photodynamic therapy(PDT)has been applied since 1980s',and people more and more concerned about PDT because of it's well-selective,of less toxicity,rapid and reliable effectiveness.As the application of new photosensitizer,improvement of laser producing machine, PDT has become a new effective option to treat NPC.
5-aminolevulinic acid(5-ALA)is one of prophotosensitizer,and then converted to HaematoporphyrinⅨ(PpⅨ)accumulating in for example tumor tissue.It is the PpⅨthat has a strong activity of photosensity.Our study is focused on feasibility of 5-ALA induced PDT in treating NPC in vivo or in vitro.
Part One Cytotoxicity of 5-ALA induced PDT on NPC cell line of CNE2
Objective:
to investigate cytotoxicity of 5-ALA induced PDT on NPC cell line of CNE2,and intracellar metabolic procedure of 5-ALA to PpⅨ,toxicity of 5-ALA,and it's otipmal time and dose of cytotoxicity on CNE2.
Method:
1.Fluorescence Spectrophotometer was applied to detect the metabolic procedure of 5-ALA in tumor cells of CNE2.
2.Laser Scanning Confocal Microscope was applied to detect the location of PpⅨafter it's precursor 5-ALA being intaked into CNE2 cells.
3.MTT[3-(4,5-dimethy1 thiazol-2-y1)-2,5-diphenyl tetrazolium bromide] assay is applied to determine cytotoxicity of 5-ALA on CNE2,effects of laser on cells without photosensitier,effects of PDT dose,effects of time of incubation of 5-ALA,effects of serum on 5-ALA PDT.
4.Flow cytometer is applied to detect cytotoxicity of 5-ALA PDT on CNE2.
5.Light microscope and transmisson electromicroscope to detect the changes of CNE2 cells after 5-ALA PDT.
Result:
1.Emission of 635nm red light was detected in tumor cells by fluorescence Spectrophotometer after exposuring to 409nm violet light.and PpⅨmerely existed intracellarly;incubation of concentration of 2mmol/L 5-ALA with tumor cells can obtain highest cytotoxicity,amount of PpⅨproduced increased is proportion positively to the time of incubation of 5-ALA.
2.Laser Scanning Confocal Microscope showed PpⅨmainly located on cell membrane and in cytoplasm.
3.the result of MTT assay showed that no effects of incubation with only 5-ALA or exposure to laser on CNE2 cells growth(P＞0.1);under a certain concentration of 5-ALA and incubation time,PDT dose of 1J,2J,5J,8J is 35.3±4.6%,55.0±3.2%,92.0±6.2%,85.5±10.9%respectively;under a certain intensity of irradiation of laser,effectiveness of PDT was positively in proportion to time of incubation with 5-ALA,and reached maximum at the time point of 8h.Animal serum affected markedly on the cytotoxicity of 5-ALA PDT,which can be weakened by increasing photosensitier dose and intensity of laser exposure.
4.Flow cytometer showed that under different dose of 5-ALA,intensity of laser exposure and with or without serum,different apoptosis rate was detected: 2mmol/L 1J 62.3%,2mmol/L 2J 74.5%;2mmol.L 10%FBS 2J 11.1%; 4mmol/L 10%FBS 2J 28.8%;6mmol/L 10%FBS 2J 75.5%.
5.Under the light microscope,CNE2 cells turned round and small.in minutes after PDT,many vacuoles can be detected in cytoplasm,with nuclear membrane getting thicker;8h after PDT,tumor cells began to break up into thin particles.Transmission electromicroscope displayed chromatin condensation and aggregation under the nuclear membrane,nuclear fragmentation and apoptosis body formation,and swelled mitochondrial was also detected.
Conclusion:
1.5-ALA-induced PpIX mainly accumulated in cell membrane and cytoplasm, 2mmol/L of 5-ALA is the optimal concentration of cytotoxicity,8h of incubation of 5-ALA got the highest cytotoxicity on CNE2.
2.It suggested that incubation of 5-ALA without laser irradiation or laser irradiation without 5-ALA administration did not induced any damage to CNE2.Higher intensity of laser irradiation strengthens cytotoxicity,which peaked under energe of 5J.It seems that under a certain concentration of 5-ALA incubation and intensity of irradiation,the cytotoxicity effects could be enhanced when incubation time with 5-ALA was lengthened,which peaked at the time point of 8h;serum inhibited markedly the effect of 5-ALA PDT.
3.It suggested that apoptosis is the main mechanism of 5-ALA cytotoxicity on CNE2 ceils,over high dose of 5-ALA or laser irradiationt could cause necrosis.
Part Two Study on the efficacy of 5-ALA-PDT for the treatment of nasopharyngeal carcinoma transplanated in Nude mice
Objective:
establish model of nude mice bearing CNE2 cell to investigate the metabolic procedure in vivo,and inhibition of tumor growth by 5-ALA PDT administrated intratumorally or intraperitoneally.
Methods:
1.Developed CNE2 cell in vitro,inoculated the cells into right axilla of nude mice subcutaneously.
2.Fluorescence Spectrophotometer was applied to detect metabolic process of 5-ALA in nude mice bearing tumor.
3.Tumor cells inoculation:when tumor beared got 0.1～0.15cm3,nude mice were divided randomly into 4 groups,group A,D:were administrated with 20%100mg/kg 5-ALA intratumorly,group B:20%100mg/Kg intraperitoneally;group C:control.3～3.5 hours after inoculation,group A,B,D were exposured to irradiation of laser(100mw/100J,630nm),and then group D were killed 24 hours later;volume of tumors beared by group A, B,C were measured on 1,3,7,10,14 days after irradiation,and the 3 groups were all killed,tumors were retained and weighed.
4.Tumor tissues of the 4 groups were detected under transmission electroscope, and were embedded in paraffin Wax,slices were prepared and studied pathologically.
Result:
1.All nude mice were transplanted with CNE2 successfully,tumor lesions all reached 0.1-0.15cm3 in 8～10 days after inoculation.
2.5-ALA mainly accumulated in tumor tissue and liver of nude mice after administration,and then turned into PpⅨ.Concentration of PpⅨwas higher in liver than in tumor tissue,peaking 1 hour after 5-ALA injection,and then began to drop,reaching the level the same as that in tumor tissue;in tumor tissue,PpⅨwas detected 1 hour after 5-ALA administration,and gradually increased to summit at the time point of 3-4 hours,dropping thereafter;a little amount of PpⅨwas detected in tissue of paratumor,muscle,lung and kidney with little detected in the organ of heart.Ratio of amount of PpⅨin normal tissue(except for liver)to that in tumor tissue is 1:2～4.
3.5-ALA-PDT did not cause any side effects in nude mice,tumor volume of the group treated was markedly bigger than the control groups;on the 14th day after PDT,tumor weight(gram)of group A,B,C3 was 1.353±0.204, 2.105±0.255,3.124±0.380,with significant difference(P=0.000).
4.Under transmission electromicroscope,tumor cells from treated group shrinked,with many vacuoles in cytoplasm,and chromatin condensation and aggregation under the nuclear membrane;nuclear fragmentation and apoptosis body formation,swelled mitochondria was also seen.Necrotic cells were also seen.Pathological slices showed in the tissues being irradiated, blood vessels dilated with diffuse hemorrhage,many vacuoles in cytoplasm, multi-lesion of necrosis and apoptosis.On 14th days after PDT,mass coagulation necrosis lesions were detected under light microscope,with shrinked nucleius,even with nucleius remains,without pigmentation with haematoxyl.
Conclusions:
1.Model of nude mice bearing CNE2 was established successfully.
2.5-ALA was distributed mainly in the tissue of liver and tumor after administration,and concentration of PpⅨpeaked 1 hour after injection of 5-ALA in liver,and 3-4 hours in tumor.
3.5-ALA PDT is a safe technique in treating NPC,showing a remarkable cytotoxicity on CNE2 in our study,with better effects in group administrated intratumorly than in group administrated intraperitoneally.
4.The results of transmission electroscope confirmed that 5-ALA PDT induced apoptosis and necrosis of CNE2 cells.
Part three Effects of 5-ALA PDT on expression of relative genes in CNE2 cell line.
Objective:to investigate expression of relative genes in transplated CNE2 cells after 5-ALA PDT.
Methods:
1.real-time quantitiy PCR was applied to detect shifts of VEGF,PCNA, Caspase3,Caspase8,Caspase9 gene in mRNA level.
2.Immunohistochemistry technique was applied to detect expression and distribution of VEGF,PCNA protein.
3.Western-blot was applied to detect expression of VEGFA,PCNA,Caspase9 protein and their state of activity.
Results:
1.In acute and chronic stage,level of expression of PCNA,Caspase9 mRNA was higher in treated group than that in control groups;
2.Results of immunohistochemistry showed that,in acute stage(1 day after administration of 5-ALA-PDT),level of VEGFA was slightly higher in group administrated intraperitoneally than that in control,while that in group administrated intratumorly was slightly lower(P＞0.05).PCNA was down-regulated in tumor cells in acute stage for abnormal metabolism,and in chronic stage,PCNA expression in survival tumor cells of treated group was higher than that in control group,but p=0.386,there is no significant statistical difference.
3.Results of Western-blotting showed that,VEGFA protein was down-regulated in chronic stage in group administrated intratumorly,while was up-regulated in acute stage;level of PCNA protein keeped stable in both acute and chronic stage;Caspase9 activated increased.
Conclusion:
1.VEGFA has no statistical difference in mRNA level;VEGFA protein was slightly up-regulated on 1st day(acute stage)and down-regulated remarkablly 14 days after PDT in chronic group,but there is no significant statistical difference between these four groups;
2.Level of PCNA mRNA expression was higher in treated group than that in control group in both acute and chronic stage(P=0.000);total amount of PCNA protein did not change,but decreased in nuclear of tumor cells in acute stage,suggesting the shift in function of PCNA protein.
3.Caspase9 mRNA expression was higher in treated group than that in control group,(P=0.021);amount of pro-Caspase9 protein dropped while Caspase9 activated increased.
5—氨基酮戊酸(5-aminolevulinic acid,5-ALA)作为具有较强光敏作用的原卟啉Ⅸ生物合成前体,5-ALA及其某些酯类近几年被用于光动力治疗,5-ALA本身不是光敏剂,是光敏剂原卟啉的生物合成前体。本课题欲从体外、体内多个方面探讨5-ALA-PDT在鼻咽癌治疗中应用的可能性。
第一部分5-ALA对体外培养人鼻咽癌细胞CNE2系的光灭活作用
目的:探索5-ALA介导的光动力治疗在体外环境中对鼻咽癌细胞的光灭活作用,及5-ALA在细胞内代谢合成PpⅨ的规律、5-ALA暗毒性、5-ALA-PDT最适作用时间、最适作用剂量等。
方法:
1荧光分光光度法测定5-ALA在肿瘤细胞中合成原卟啉的情况;
2荧光倒置相差显微镜观察CNE2细胞吸收后5-ALA合成PpⅨ在细胞内的定位;
3 MTT细胞毒实验检测5-ALA对细胞的暗毒性、单纯辐照对细胞的影响、照光剂量对PDT的影响、不同5-ALA孵育时间的影响、血清对5-ALA-PDT的影响;
4流式细胞术检测5-ALA-PDT对肿瘤细胞的杀伤作用;
5光镜、透射电镜下观察5-ALA-PDT后细胞形态学的改变。
结果:
1.荧光分光光度法检测发射荧光强度观察PpⅨ的生成量:409nm的蓝紫光能激发细胞内合成的PpⅨ发射出635nm波长的红光,结果显示:产生的PpⅨ只存在于细胞中;2mmol/L5-ALA体外孵育浓度已达饱和;5-ALA吸收后在细胞内产生的PpⅨ量随时间的延长而逐渐增加,10小时前PpⅨ随时间增长得最快。
2.荧光倒置相差显微镜观察:5-ALA被CNE2细胞吸收后产生的PpⅨ主要存在于细胞膜和胞浆中。
3.MTT细胞毒实验:单纯5-ALA孵育及单纯冷光源激光辐照对肿瘤细胞的生长在10小时内几乎无影响(p＞0.1);5-ALA孵育浓度和时间一定时,1、2、5、8J辐照剂量的抑制率分别是:1J 34.3±4.6;2J 55.0±3.2;5J 92.0±6.2:8J 85.5±10.9;在光照剂量和强度一定的情况下,延长5-ALA药物的孵育时间可以明显提高PDT效应,但8小时为最长孵育时间,再延长时间对PDT影响不大;动物血清对5-ALA-PDT效应存在着明显的抑制作用,这种抑制作用可以通过增加5-ALA浓度,提高辐照剂量等而得到进一步增强。
4.流式细胞术检测不同浓度5-ALA和辐照剂量及血清存在下诱导的细胞凋亡率:2mmol/L 1J 62.3%;2mmol/L 2J 74.5%;2mmol/L 10%FBS2J 11.1%:4mmol/L 10%FBS 2J 28.8%;6mmol/L 10%FBS 2J 75.5%。
5.光镜下观察5-ALA-PDT后细胞形态学改变快,数分钟内即可在普通倒置相差显微镜下观察到细胞变圆、变小,细胞内大量的空泡形成、核膜着色加深,8小时后细胞分解成细颗粒状,部分细胞结构尚存。透射电镜下细胞染色质边集凝聚、断裂、核膜出泡及凋亡小体形成,胞浆内线粒体肿胀脱颗粒等。
结论:
1.5-ALA在细胞内合成的PpⅨ主要存在于细胞胞浆及包膜中,2mmol/L为体外最适浓度;
2.单用5-ALA孵育对细胞无毒性;单独辐照对细胞生长无影响;体外适量增大照光剂量可增强PDT对细胞的灭活作用,光剂量5J时达峰值;在5-ALA孵育浓度一致和照光剂量相等的情况下,延长ALA孵育时间可以增强PDT损伤效应;血清对5-ALA-PDT有明显的竞争性抑制作用;
3.诱导细胞凋亡为5-ALA-PDT杀伤细胞的主要作用机制,但当药物剂量过高、光剂量太大时,则诱导细胞坏死。
第二部分5-ALA对裸鼠人鼻咽癌移植瘤的光动力疗效
目的:建立裸鼠人鼻咽癌CNE2荷瘤模型,摸索5-ALA在体内的代谢情况,研究局部和腹腔给药方式下,5-ALA-PDT对肿瘤生长的抑制作用。
方法:
1.体外培养人鼻咽癌CNE2细胞,以2～5×10~6/0.2ml接种于裸鼠右腋下。
2.荧光分光光度法检测5-ALA在荷瘤小鼠体内各脏器、组织中合成PpⅨ的情况。
3.接种人鼻咽癌CNE2细胞,当肿瘤大小达0.1-0.15cm~3时随机分成4组,A、D组局部给予20%5-ALA100mg.kg~(-1),B组腹腔给予20%5-ALA100mg.kg~(-1),C组为对照组。3～3.5小时后A、B、D接受100mw.100J~(-1)630nm激光照射,24h后D组断颈处死;A、B、C组PDT处理后1、3、7、10、14d用游标卡尺测量肿瘤大小,14d断颈处死,称量3组瘤重。
4.取4组肿瘤组织制蜡块做病理切片、电镜检查等。
结果:
1.人鼻咽癌CNE2细胞接种成功率达100%,8～10天肿瘤大小可达0.1-0.15cm~3。
2.5-ALA吸收后主要在于肿瘤组织和肝脏中积聚合成PpⅨ,且肝脏组织中的含量高于肿瘤组织。PpⅨ在肝脏内一小时即达高峰,后逐渐下降,5小时与肿瘤组织含量基本一致;而肿瘤组织中的PpⅨ一小时起即可检测到,后逐渐升高,3～4小时左右达峰值,后逐渐下降,瘤旁粘膜、肌肉组织及肺、肾可少量吸收光敏剂而产生PpⅨ,而心脏几乎不含PpⅨ,正常组织除肝脏外与肿瘤组织的吸收比约为1:2～4。
3.5-ALA-PDT对小鼠无明显毒副反应,治疗后1天起治疗组与对照肿瘤体积就有明显的差异,14天后A、B、C3组肿瘤重量(g)分别是1.353±0.204、2.105±0.255、3.124±0.380,P=0.000;
4.透射电镜观察5-ALA-POT治疗后,细胞体积明显缩小,胞浆内出现大量空泡,为肿胀的线粒体,线粒体嵴短小而显示不清,核内染色质凝集、致密,呈颗粒、块状均质分布在核膜内侧,电子密度高,核中心染色质消失淡染,少数核膜出泡形成凋亡小体,存在与其他细胞周围或被吞噬,呈现典型的凋亡表现。部分边集的染色质断裂,到逐渐溶解消失。同时也存在部分坏死细胞,表现为细胞明显变性、解离、胞质疏松、膨胀,细胞膜破坏,线粒体脱颗粒、消失。病理切片显示PDT治疗后一天,局部血管扩张及弥漫性出血,细胞胞浆内出现大量空泡和多处灶状坏死及凋亡,。PDT治疗后14天,镜下见大片凝固性坏死,细胞核固缩,甚至只残留核形,而无嗜苏木素着色。
结论:
1.小鼠人鼻咽癌荷瘤模型建立成功;
2.5-ALA体内吸收后合成的PpⅨ主要分布于肝脏和肿瘤中,PpⅨ在肝脏中1小时内达峰值,在肿瘤中3小时左右达峰值;
3.5-ALA-PDT是安全可靠的治疗方法,能明显抑制人鼻咽癌肿瘤的生长,且局部治疗组明显优于全身治疗组;
4.透射电镜和病理切片证实5-ALA-PDT诱导肿瘤细胞凋亡和坏死。
第三部分5-ALA-PDT后血管生成、增殖能力及凋亡途径的探讨
目的:探讨5-ALA-PDT后血管生成、增殖能力及凋亡途径上的改变
方法:
1.实时荧光定量PCR检测血管内皮生长因子(vascular endothelial growthfactor,VEGF)、增殖细胞核抗原(proliferation cell nuclear antigen,PCNA)、半胱氨酸.天冬氨酸蛋白激酶-3、-8、-9(Caspase3、Caspase8、Caspase9)等基因mRNA水平的改变
2.免疫组化检测VEGFA、PCNA的蛋白表达水平及在细胞中的定位
3.Western-blot免疫印记法检测VEGFA、PCNA、Caspase9蛋白表达水平的差异及激酶激活状态的差异
结果:
1.在mRNA检测水平上治疗组1d及14d PCNA、Caspase9均高于对照组;
2.免疫组化检测显示VEGFA在治疗后急性期(1d)及全身给药组略高于对照组,而局部给药组略低于对照组,暂无明显统计学差异。PCNA在PDT后1d由于肿瘤细胞的代谢异常,胞核中的PCNA表达下调,核膜周边着色,PDT后14d存活的肿瘤细胞PCNA略高于对照组,p=0.386,暂无明显统计学差异。
3.Westem-blotting检测:局部治疗组14dVEGFA蛋白表达明显下调(p=0.000),PDT后1d组略上调;PCNA总蛋白含量无明显差异;Caspase9的原型减少,激活形式明显增多(p=0.015)。
结论:
1.VEGFA在mRNA水平无明显统计学差异,蛋白表达水平局部治疗组PDT后14天明显下调,而PDT后1天略为上调;
2.PCNA在mRNA水平治疗组1d及14d均明显高于对照组,有统计学差异;总蛋白水平无明显差异,但PDT后1天分布在胞核中的PCNA减少,提示功能上存在差异。
3.Caspase9在mRNA水平治疗组均高于对照组;蛋白水平原型的Caspase9减少,而激活形式增多。
Nasopharyngeal carcinoma(NPC)is very common in southeast of China,especially in Guangdong and Guangxi province,with a incidence up to 30/10~5.Most of the NPC patients are diagnosed in middle and advanced stage because of its early atypical symptoms,and the 5-yearl-survival rate is only 50%～70%after radiotherapy and chemotherapy,with severe complications. Thus other new method should be taken to improve the survival rate with less severe complications.Photodynamic therapy(PDT)has been applied since 1980s',and people more and more concerned about PDT because of it's well-selective,of less toxicity,rapid and reliable effectiveness.As the application of new photosensitizer,improvement of laser producing machine, PDT has become a new effective option to treat NPC.
5-aminolevulinic acid(5-ALA)is one of prophotosensitizer,and then converted to HaematoporphyrinⅨ(PpⅨ)accumulating in for example tumor tissue.It is the PpⅨthat has a strong activity of photosensity.Our study is focused on feasibility of 5-ALA induced PDT in treating NPC in vivo or in vitro.
Part One Cytotoxicity of 5-ALA induced PDT on NPC cell line of CNE2
Objective:
to investigate cytotoxicity of 5-ALA induced PDT on NPC cell line of CNE2,and intracellar metabolic procedure of 5-ALA to PpⅨ,toxicity of 5-ALA,and it's otipmal time and dose of cytotoxicity on CNE2.
Method:
1.Fluorescence Spectrophotometer was applied to detect the metabolic procedure of 5-ALA in tumor cells of CNE2.
2.Laser Scanning Confocal Microscope was applied to detect the location of PpⅨafter it's precursor 5-ALA being intaked into CNE2 cells.
3.MTT[3-(4,5-dimethy1 thiazol-2-y1)-2,5-diphenyl tetrazolium bromide] assay is applied to determine cytotoxicity of 5-ALA on CNE2,effects of laser on cells without photosensitier,effects of PDT dose,effects of time of incubation of 5-ALA,effects of serum on 5-ALA PDT.
4.Flow cytometer is applied to detect cytotoxicity of 5-ALA PDT on CNE2.
5.Light microscope and transmisson electromicroscope to detect the changes of CNE2 cells after 5-ALA PDT.
Result:
1.Emission of 635nm red light was detected in tumor cells by fluorescence Spectrophotometer after exposuring to 409nm violet light.and PpⅨmerely existed intracellarly;incubation of concentration of 2mmol/L 5-ALA with tumor cells can obtain highest cytotoxicity,amount of PpⅨproduced increased is proportion positively to the time of incubation of 5-ALA.
2.Laser Scanning Confocal Microscope showed PpⅨmainly located on cell membrane and in cytoplasm.
3.the result of MTT assay showed that no effects of incubation with only 5-ALA or exposure to laser on CNE2 cells growth(P＞0.1);under a certain concentration of 5-ALA and incubation time,PDT dose of 1J,2J,5J,8J is 35.3±4.6%,55.0±3.2%,92.0±6.2%,85.5±10.9%respectively;under a certain intensity of irradiation of laser,effectiveness of PDT was positively in proportion to time of incubation with 5-ALA,and reached maximum at the time point of 8h.Animal serum affected markedly on the cytotoxicity of 5-ALA PDT,which can be weakened by increasing photosensitier dose and intensity of laser exposure.
4.Flow cytometer showed that under different dose of 5-ALA,intensity of laser exposure and with or without serum,different apoptosis rate was detected: 2mmol/L 1J 62.3%,2mmol/L 2J 74.5%;2mmol.L 10%FBS 2J 11.1%; 4mmol/L 10%FBS 2J 28.8%;6mmol/L 10%FBS 2J 75.5%.
5.Under the light microscope,CNE2 cells turned round and small.in minutes after PDT,many vacuoles can be detected in cytoplasm,with nuclear membrane getting thicker;8h after PDT,tumor cells began to break up into thin particles.Transmission electromicroscope displayed chromatin condensation and aggregation under the nuclear membrane,nuclear fragmentation and apoptosis body formation,and swelled mitochondrial was also detected.
Conclusion:
1.5-ALA-induced PpIX mainly accumulated in cell membrane and cytoplasm, 2mmol/L of 5-ALA is the optimal concentration of cytotoxicity,8h of incubation of 5-ALA got the highest cytotoxicity on CNE2.
2.It suggested that incubation of 5-ALA without laser irradiation or laser irradiation without 5-ALA administration did not induced any damage to CNE2.Higher intensity of laser irradiation strengthens cytotoxicity,which peaked under energe of 5J.It seems that under a certain concentration of 5-ALA incubation and intensity of irradiation,the cytotoxicity effects could be enhanced when incubation time with 5-ALA was lengthened,which peaked at the time point of 8h;serum inhibited markedly the effect of 5-ALA PDT.
3.It suggested that apoptosis is the main mechanism of 5-ALA cytotoxicity on CNE2 ceils,over high dose of 5-ALA or laser irradiationt could cause necrosis.
Part Two Study on the efficacy of 5-ALA-PDT for the treatment of nasopharyngeal carcinoma transplanated in Nude mice
Objective:
establish model of nude mice bearing CNE2 cell to investigate the metabolic procedure in vivo,and inhibition of tumor growth by 5-ALA PDT administrated intratumorally or intraperitoneally.
Methods:
1.Developed CNE2 cell in vitro,inoculated the cells into right axilla of nude mice subcutaneously.
2.Fluorescence Spectrophotometer was applied to detect metabolic process of 5-ALA in nude mice bearing tumor.
3.Tumor cells inoculation:when tumor beared got 0.1～0.15cm3,nude mice were divided randomly into 4 groups,group A,D:were administrated with 20%100mg/kg 5-ALA intratumorly,group B:20%100mg/Kg intraperitoneally;group C:control.3～3.5 hours after inoculation,group A,B,D were exposured to irradiation of laser(100mw/100J,630nm),and then group D were killed 24 hours later;volume of tumors beared by group A, B,C were measured on 1,3,7,10,14 days after irradiation,and the 3 groups were all killed,tumors were retained and weighed.
4.Tumor tissues of the 4 groups were detected under transmission electroscope, and were embedded in paraffin Wax,slices were prepared and studied pathologically.
Result:
1.All nude mice were transplanted with CNE2 successfully,tumor lesions all reached 0.1-0.15cm3 in 8～10 days after inoculation.
2.5-ALA mainly accumulated in tumor tissue and liver of nude mice after administration,and then turned into PpⅨ.Concentration of PpⅨwas higher in liver than in tumor tissue,peaking 1 hour after 5-ALA injection,and then began to drop,reaching the level the same as that in tumor tissue;in tumor tissue,PpⅨwas detected 1 hour after 5-ALA administration,and gradually increased to summit at the time point of 3-4 hours,dropping thereafter;a little amount of PpⅨwas detected in tissue of paratumor,muscle,lung and kidney with little detected in the organ of heart.Ratio of amount of PpⅨin normal tissue(except for liver)to that in tumor tissue is 1:2～4.
3.5-ALA-PDT did not cause any side effects in nude mice,tumor volume of the group treated was markedly bigger than the control groups;on the 14th day after PDT,tumor weight(gram)of group A,B,C3 was 1.353±0.204, 2.105±0.255,3.124±0.380,with significant difference(P=0.000).
4.Under transmission electromicroscope,tumor cells from treated group shrinked,with many vacuoles in cytoplasm,and chromatin condensation and aggregation under the nuclear membrane;nuclear fragmentation and apoptosis body formation,swelled mitochondria was also seen.Necrotic cells were also seen.Pathological slices showed in the tissues being irradiated, blood vessels dilated with diffuse hemorrhage,many vacuoles in cytoplasm, multi-lesion of necrosis and apoptosis.On 14th days after PDT,mass coagulation necrosis lesions were detected under light microscope,with shrinked nucleius,even with nucleius remains,without pigmentation with haematoxyl.
Conclusions:
1.Model of nude mice bearing CNE2 was established successfully.
2.5-ALA was distributed mainly in the tissue of liver and tumor after administration,and concentration of PpⅨpeaked 1 hour after injection of 5-ALA in liver,and 3-4 hours in tumor.
3.5-ALA PDT is a safe technique in treating NPC,showing a remarkable cytotoxicity on CNE2 in our study,with better effects in group administrated intratumorly than in group administrated intraperitoneally.
4.The results of transmission electroscope confirmed that 5-ALA PDT induced apoptosis and necrosis of CNE2 cells.
Part three Effects of 5-ALA PDT on expression of relative genes in CNE2 cell line.
Objective:to investigate expression of relative genes in transplated CNE2 cells after 5-ALA PDT.
Methods:
1.real-time quantitiy PCR was applied to detect shifts of VEGF,PCNA, Caspase3,Caspase8,Caspase9 gene in mRNA level.
2.Immunohistochemistry technique was applied to detect expression and distribution of VEGF,PCNA protein.
3.Western-blot was applied to detect expression of VEGFA,PCNA,Caspase9 protein and their state of activity.
Results:
1.In acute and chronic stage,level of expression of PCNA,Caspase9 mRNA was higher in treated group than that in control groups;
2.Results of immunohistochemistry showed that,in acute stage(1 day after administration of 5-ALA-PDT),level of VEGFA was slightly higher in group administrated intraperitoneally than that in control,while that in group administrated intratumorly was slightly lower(P＞0.05).PCNA was down-regulated in tumor cells in acute stage for abnormal metabolism,and in chronic stage,PCNA expression in survival tumor cells of treated group was higher than that in control group,but p=0.386,there is no significant statistical difference.
3.Results of Western-blotting showed that,VEGFA protein was down-regulated in chronic stage in group administrated intratumorly,while was up-regulated in acute stage;level of PCNA protein keeped stable in both acute and chronic stage;Caspase9 activated increased.
Conclusion:
1.VEGFA has no statistical difference in mRNA level;VEGFA protein was slightly up-regulated on 1st day(acute stage)and down-regulated remarkablly 14 days after PDT in chronic group,but there is no significant statistical difference between these four groups;
2.Level of PCNA mRNA expression was higher in treated group than that in control group in both acute and chronic stage(P=0.000);total amount of PCNA protein did not change,but decreased in nuclear of tumor cells in acute stage,suggesting the shift in function of PCNA protein.
3.Caspase9 mRNA expression was higher in treated group than that in control group,(P=0.021);amount of pro-Caspase9 protein dropped while Caspase9 activated increased.
引文
[1]McDermott A L,Dutt S N,Watkinson J C.The aetiology of nasopharyngeal carcinoma.[J].Clin Otolaryngol Allied Sci,2001,26(2):82-92.
[2]Henderson B W,Dougherty T J.How does photodynamic therapy work?[J].Photochem Photobiol,1992,55(1):145-157.
[3]Zumbraegel A,Bichler K H,Krause F S,et al.The photodynamic diagnosis(PDD)for early detection of carcinoma and dysplasia of the bladder.[J].Adv Exp Med Biol,2003,539(Pt A):61-66.
[4]Athar M,Elmets C A,Bickers D R,et al.A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization.Activation of the xanthine oxidase pathway.[J].J Clin Invest,1989,83(4):1137-1143.
[5]Rittenhouse-Diakun K,Van L H,Morgan J,et al.The role of transferrin receptor(CD71)in photodynamic therapy of activated and malignant lymphocytes using the heme precursor delta-aminolevulinic acid(ALA).[J].Photochem Photobiol,1995,61(5):523-528.
[6]Peng Q,Warloe T,Berg K,et al.5-Aminolevulinic acid-based photodynamic therapy.Clinical research and future challenges.[J].Cancer,1997,79(12):2282-2308.
[7]Ratcliffe S L,Matthews E K.Modification of the photodynamic action of delta-aminolaevulinic acid(ALA)on rat pancreatoma cells by mitochondrial benzodiazepine receptor ligands.[J].Br J Cancer,1995,71(2):300-305.
[8]Iinuma S,Farshi S S,Ortel B,et al.A mechanistic study of cellular photodestruction with 5-aminolaevulinic acid-induced porphyrin.[J].Br J Cancer,1994,70(1):21-28.
[9]Manivasager V,Heng P W,Hao J,et al.A study of 5-aminolevulinic acid and its methyl ester used in in vitro and in vivo systems of human bladder cancer.[J].Int J Oncol,2003,22(2):313-318.
[1]Grosjean P,Savary J F,Mizeret J,et al.Photodynamic therapy for cancer of the upper aerodigestive tract using tetra(m-hydroxyphenyl)chlorin.[J].J Clin Laser Med Surg,1996,14(5):281-287.
[2]Maier A,Yomaselli F,Matzi V,et al.Photosensitization with hematoporphyrin derivative compared to 5-aminolaevulinic acid for photodynamic therapy of esophageal carcinoma.[J].Ann Thorac Surg,2001,72(4):1136-1140.
[3]Mimura S,Narahara H,Uehara H,et al.[Photodynamic therapy for gastric cancer][J].Gan To Kagaku Ryoho,1996,23(1):41-46.
[4]Wierrani F,Kubin A,Jindra R,et al.5-aminolevulinic acid-mediated photodynamic therapy of intraepithelial neoplasia and human papillomavirus of the uterine cervix—a new experimental approach.[J].Cancer Detect Prey,1999,23(4):351-355.
[5]Blume J E,Oseroff A R.Aminolevulinic acid photodynamic therapy for skin cancers.[J].Dermatol Clin,2007,25(1):5-14.
[6]Braathen L R,Szeimies R M,Basset-Seguin N,et al.Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer:an international consensus.International Society for Photodynamic Therapy in Dermatology,2005.[J].J Am Acad Dennatol,2007,56(1):125-143.
[7]Henderson B W,Busch T M,Vaughan L A,et al.Photofrin photodynamic therapy can significantly deplete or preserve oxygenation in human basal cell carcinomas during treatment,depending on fluence rate.[J].Cancer Res,2000,60(3):525-529.
[8]Rittenhouse-Diakun K,Van L H,Morgan J,et al.The role of transferrin receptor(CD71)in photodynamic therapy of activated and malignant lymphocytes using the heme precursor delta-aminolevulinic acid (ALA).[J].Photochem Photobiol,1995,61(5):523-528.
[9]Peng Q,Warloe T,Berg K,et al.5-Aminolevulinic acid-based photodynamic therapy.Clinical research and future challenges.[J].Cancer,1997,79(12):2282-2308.
[10]Manivasager V,Heng P W,Hao J,et al.A study of 5-aminolevulinic acid and its methyl ester used in in vitro and in vivo systems of human bladder cancer.[J].Int J Oncol,2003,22(2):313-318.
[11]Wu S M,Ren Q G,Zhou M O,et al.Protoporphyrin Ⅸ production and its photodynamic effects on glioma cells,neuroblastoma cells and normal cerebellar granule cells in vitro with 5-aminolevulinic acid and its hexylester.[J].Cancer Lett,2003,200(2):123-131.
[12]Ren Q G,Wu S M,Peng Q,et al.Comparison of 5-aminolevulinic acid and its hexylester mediated photodynamic action on human hepatoma cells.[J].Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao(Shanghai),2002,34(5):650-654.
[13]Alexiades-Armenakas M.Aminolevulinic acid photodynamic therapy for actinic keratoses/actinic cheilitis/acne:vascular lasers.[J].Dermatol Clin,2007,25(1):25-33.
[14]Becker D M,Kramer S,Viljoen J D.Delta-aminolevulinic acid uptake by rabbit brain cerebral cortex.[J].J Neurochem,1974,23(5):1019-1023.
[15]Kessel D,Antolovich M,Smith K M.The role of the peripheral benzodiazepine receptor in the apoptotic response to photodynamic therapy.[J].Photochem Photobiol,2001,74(2):346-349.
[16]Brennan M J,Cantrill R C.Delta-aminolaevulinic acid is a potent agonist for GABA autoreceptors.[J].Nature,1979,280(5722):514-515.
[17]McLoughlin J L,Cantrill R C.The effect of delta-aminolaevulinic acid on the high affinity uptake of aspartic acid by rat brain synaptosomes.[J].Gen Pharmacol,1984,15(6):553-555.
[18]Cheeks C,Wedeen R P.Renal tubular transport of delta-aminolevulinic acid in rat.[J].Proc Soc Exp Biol Med,1986,181(4):596-601.
[19]Doring F,Walter J,Will J,et al.Delta-aminolevulinic acid transport by intestinal and renal peptide transporters and its physiological and clinical implications.[J].J Clin Invest,1998,101(12):2761-2767.
[20]Brennan M J,Cantrill R C.The effects of delta-aminolaevulinic acid on the uptake and efflux of amino acid neurotransmitters in rat brain synaptosomes.[J].J Neurochem,1979,33(3):721-725.
[21]Latkowski B,Gryczynski M,Murlewska A.[Use of sensitizers and photo laser for diagnosis and treatment of malignant tumors][J].Otolaryngol Pol,1995,49 Suppl 20:205-208.
[22]Henderson B W,Dougherty T J.How does photodynamic therapy work?[J].Photochem Photobiol,1992,55(1):145-157.
[23]刘慧龙、刘凡光,影响光动力疗法的几个主要因素.[J].中国激光医学杂志.2002,11(2):121-124
[24]张苏娟,张镇西,蒋大宗.基于氨乙酰(ALA)脂类衍生物的光动力疗法(PDT).[J].J Biomed Eng.2002,19(2):310-314。
[1]Bedwell J,MacRobert A J,Phillips D,et al.Fluorescence distribution and photodynamic effect of ALA-induced PP Ⅸ in the DMH rat colonic tumour model.[J].Br J Cancer,1992,65(6):818-824.
[2]Henderson B W,Vaughan L,Bellnier D A,et al.Photosensitization of murine tumor,vasculature and skin by 5-aminolevulinic acid-induced porphyrin.[J].Photochem Photobiol,1995,62(4):780-789.
[3]Loh C S,MacRobert A J,Bedwell J,et al.Oral versus intravenous administration of 5-aminolaevulinic acid for photodynamic therapy.[J].Br J Cancer,1993,68(1):41-51.
[4]Orenstein A,Kostenich G,Roitman L,et al.A comparative study of tissue distribution and photodynamic therapy selectivity of chlorin e6,Photofrin Ⅱand ALA-induced protoporphyrin Ⅸ in a colon carcinoma model.[J].Br J Cancer,1996,73(8):937-944.
[5]Xu S,Menon I A,Becker M A,et al.Endogenous porphyrins in murine skin and transplanted PAM-212 squamous cell carcinoma tissues after injection of delta-aminolevulinic acid.[J].Chin Med J(Engl),1995,108(4):286-290.
[6]Lofgren L A,Ronn A M,Nouri M,et al.Efficacy of intravenous delta-aminolaevulinic acid photodynamic therapy on rabbit papillomas.[J].Br J Cancer,1995,72(4):857-864.
[7]Regula J,Ravi B,Bedwell J,et al.Photodynamic therapy using 5-aminolaevulinic acid for experimental pancreatic cancer—prolonged animal survival.[J].Br J Cancer,1994,70(2):248-254.
[8]van H R,Hekking-Weijma J M,Wilson J H,et al.Adjuvant intraoperative photodynamic therapy diminishes the rate of local recurrence in a rat mammary tumour model.[J].Br J Cancer,1995,71(4):733-737.
[9]Lilge L,Olivo M C,Schatz S W,et al.The sensitivity of normal brain and intracranially implanted VX2 tumour to interstitial photodynamic therapy.[J].Br J Cancer,1996,73(3):332-343
[10]Abels C,Heil P,Dellian M,et al.In vivo kinetics and spectra of 5-aminolaevulinic acid-induced fluorescence in an amelanotic melanoma of the hamster.[J].Br J Cancer,1994,70(5):826-833
[11]Hermes-Lima M.How do Ca2+ and 5-aminolevulinic acid-derived oxyradicals promote injury to isolated mitochondria?[J].Free Radic Biol Med,1995,19(3):381-390.
[12]Bermudez M M,Correa G S,Chianelli M S,et al.Evidence that 4-aminobutyric acid and 5-aminolevulinic acid share a common transport system into Saccharomyces cerevisiae.[J].Int J Biochem Cell Biol,1995,27(2):169-173.
[13]Oteiza P I,Kleinman C G,Demasi M,et al.5-Aminolevulinic acid induces iron release from ferritin.[J].Arch Biochem Biophys,1995,316(1):607-611.
[14]Hermes-Lima M,Castilho R F,Valle V G,et al.Calcium-dependent mitochondrial oxidative damage promoted by 5-aminolevulinic acid.[J].Biochim Biophys Acta,1992,1180(2):201-206.
[15]Hermes-Lima M,Valle V G,Vercesi A E,et al.Damage to rat liver mitochondria promoted by delta-aminolevulinic acid-generated reactive oxygen species:connections with acute intermittent porphyria and lead-poisoning.[J].Biochim Biophys Acta,1991,1056(1):57-63.
[16]Sustained high plasma 5-aminolaevulinic acid concentration in a volunteer:no porphyric symptoms.[J].1992,22(6):407-411.
[17]van V N,de B H,Berg R J,et al.Kinetics and localisation of PpIX fluorescence after topical and systemic ALA application,observed in skin and skin tumours of UVB-treated mice.[J].Br J Cancer,1996,73(7):925-930.
[18]Peng Q,Warloe T,Moan J,et al.Distribution of 5-aminolevulinic acid-induced porphyrins in noduloulcerative basal cell carcinoma.[J].Photochem Photobiol,1995,62(5):906-913.
[19]Dolmans D E,Fukumura D,Jain R K.Photodynamic therapy for cancer.[J].Nat Rev Cancer,2003,3(5):380-387.
[20]Janda P,Sroka R,Baumgartner R,et al.Laser treatment of hyperplastic inferior nasal turbinates:a review.[J].Lasers Surg Med,2001,28(5):404-413.
[21]Chan W H,Yu J S,Yang S D.Apoptotic signalling cascade in photosensitized human epidermal carcinoma A431 cells:involvement of singlet oxygen,c-Jun N-terminal kinase,caspase-3 and p21-activated kinase 2.[J].Biochem J,2000,351(Pt 1):221-232.
[22]Zhuang S,Demirs J T,Kochevar I E.p38 mitogen-activated protein kinase mediates bid cleavage,mitochondrial dysfunction,and caspase-3activation during apoptosis induced by singlet oxygen but not by hydrogen peroxide.[J].J Biol Chem,2000,275(34):25939-25948.
[23]Grebenova D,Kuzelova K,Smetana K,et al.Mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by 5-aminolevulinic acid-based photodynamic therapy in HL60 leukemia cells.[J].J Photochem Photobiol B,2003,69(2):71-85.
[24]Karbownik M,Reiter R J.Melatonin protects against oxidative stress caused by delta-aminolevulinic acid:implications for cancer reduction.[J].Cancer Invest,2002,20(2):276-286.
[25]Henderson B W,Fingar V H.Oxygen limitation of direct tumor cell kill during photodynamic treatment of a murine tumor model.[J].Photochem Photobiol,1989,49(3):299-304.
[26]Canti G,Marelli O,Ricci L,et al.Haematoporphyrin-treated murine lymphocytes:in vitro inhibition of DNA synthesis and light-mediated inactivation of ceils responsible for GVHR.[J].Photochem Photobiol,1981,34(5):589-594.
[27]Korbelik M.Induction of tumor immunity by photodynamic therapy.[J].J Clin Laser Med Surg,1996,14(5):329-334.
[1] Schuitmaker J J, Baas P, van L H, et al. Photodynamic therapy: a promising new modality for the treatment of cancer.[J]. J Photochem Photobiol B, 1996, 34(1): 3-12.
[2] Ochsner M. Photophysical and photobiological processes in the photo- dynamic therapy of tumours. [J]. J Photochem Photobiol B, 1997,39(1): 1-18.
[3] Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.[J]. Cell, 1996, 86(3): 353—364.
[4] Klagsbrun M, Soker S. VEGF/VPF: the angiogenesis factor found?[J]. Curr Biol, 1993,3(10): 699-702.
[5] Dvorak H F, Brown L F, Detmar M, et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.[J]. Am JPathol, 1995,146(5): 1029-1039.
[6] Osiecka B J, Ziolkowski P, Gamian E, et al. Determination of vascular-endothelial growth factor levels in serum from tumor-bearing BALB/c mice treated with photodynamic therapy.[J]. Med Sci Monit, 2003,9(4): 110—114.
[7] Schmidt-Erfurth U, Schlotzer-Schrehard U, Cursiefen C, et al. Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor.[J]. Invest Ophthalmol Vis Sci, 2003, 44(10): 4473-4480.
[8] Solban N, Selbo P K, Sinha A K, et al. Mechanistic investigation and implications of photodynamic therapy induction of vascular endothelial growth factor in prostate cancer.[J]. Cancer Res, 2006, 66(11): 5633—5640.
[9] Zhang X, Jiang F, Zhang Z G, et al. Low-dose photodynamic therapy increases endothelial cell proliferation and VEGF expression in nude mice brain.[J]. Lasers Med Sci, 2005, 20(2): 74-79.
[10] Ferrario A, von T K, Rucker N, et al. Antiangiogenic treatment enhances photodynamic therapy responsiveness in a mouse mammary carcinoma. [J]. Cancer Res, 2000, 60(15): 4066-4069.
[11] Dimitroff C J, Klohs W, Sharma A, et al. Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: implications for combination treatment with photodynamic therapy.[J]. Invest New Drugs, 1999, 17(2): 121-135.
[12] Zhou Q, Olivo M, Lye K Y, et al. Enhancing the therapeutic responsiveness of photodynamic therapy with the antiangiogenic agents SU5416 and SU6668 in murine nasopharyngeal carcinoma models.[J]. Cancer Chemother Pharmacol, 2005, 56(6): 569-577.
[13] Abels C, Heil P, Dellian M, et al. In vivo kinetics and spectra of 5-aminolaevulinic acid-induced fluorescence in an amelanotic melanoma of the hamster.[J]. Br J Cancer, 1994, 70(5): 826-833.
[14] Martin A, Tope W D, Grevelink J M, et al. Lack of selectivity of protoporphyrin IX fluorescence for basal cell carcinoma after topical application of 5-aminolevulinic acid: implications for photodynamic treatment.[J]. Arch Dermatol Res, 1995, 287(7): 665—674.
[15] Miyachi K, Fritzler M J, Tan E M. Autoantibody to a nuclear antigen in proliferating cells.[J]. J Immunol, 1978, 121(6): 2228-2234.
[16] Ducoux M, Urbach S, Baldacci G, et al. Mediation of proliferating cell nuclear antigen (PCNA)-dependent DNA replication through a conserved p21(Cip1)-like PCNA-binding motif present in the third subunit of human DNA polymerase delta.[J].J Biol Chem,2001,276(52):49258-49266.
[17]Parrilla-Castellar E R,Arlander S J,Karnitz L.Dial 9-1-1 for DNA damage:the Rad9-Husl-Radl(9-1-1)clamp complex.[J].DNA Repair (Amst),2004,3(8-9):1009-1014.
[18]Friedrich-Heineken E,Toueille M,Yarmler B,et al.The two DNA clamps Rad9/Rad1/Hus1 complex and proliferating cell nuclear antigen differentially regulate flap endonuclease 1 activity.[J].J Mol Biol,2005,353(5):980-989.
[19]Skibbens R V,Corson L B,Koshland D,et al.Ctf7p is essential for sister chromatid cohesion and links mitotic chromosome structure to the DNA replication machinery.[J].Genes Dev,1999,13(3):307-319.
[20]Chuang L S,Ian H I,Koh T W,et al.Human DNA-(cytosine-5)methyltransferase-PCNA complex as a target for p21WAFI.[J].Science,1997,277(5334):1996-2000.
[21]Haupt S,Berger M,Goldberg Z,et al.Apoptosis - the p53 network.[J].J Cell Sci,2003,116(Pt 20):4077-4085.
[22]Lukomski M,Jozefowicz-Korczynska M,Kobos J.[The prognostic value of modified quantitative classification and expression of monoclonal antibodies against PCNA in laryngeal neoplasm(introduction)][J].Otolaryngol Pol,1995,49 Suppl 20:87-92.
[23]Golusinski W,Szmeja Z,Olofsson J,et al.[Diagnostic and prognostic value of p53 oncogene and the selected neoplastic markers(Ki67,PCNA,DNA ploidy)of the ultrastructure in patients with laryngeal cancer][J].Otolaryngol Pol,1996,50(6):607-617.
[24]Kram A,Domagala W.Proliferating cell nuclear antigen(PCNA) expression in laryngeal squamous cell carcinomas.An immuno- histochemical study.[J].Pol J Pathol,1996,47(4):183-187.
[25]Welkoborsky H J,Hinni M,Dienes H P,et al.Predicting recurrence and survival in patients with laryngeal cancer by means of DNA cytometry,tumor front grading,and proliferation markers.[J].Ann Otol Rhinol Laryngol,1995,104(7):503-510.
[26]Almeida R D,Gomes E R,Carvalho A P,et al.Calpains are activated by photodynamic therapy but do not contribute to apoptotic tumor cell death.[J].Cancer Lett,2004,216(2):183-189.
[27]Wallach D,Varfolomeev E E,Malinin N L,et al.Tumor necrosis factor receptor and Fas signaling mechanisms.[J].Annu Rev Immunol,1999,17:331-367.
[28]Apoptosomes:engines for caspase activation.[J].2002,14(6):715-720.
[29]Kim T H,Zhao Y,Barber M J,et al.Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax.[J].J Biol Chem,2000,275(50):39474-39481.
[30]Ahmad N,Gupta S,FeTes D K,et al.Involvement ofFas(APO-1/CD-95)during photodynamic-therapy-mediated apoptosis in human epidermoid carcinoma A431 cells.[J].J Invest Dermatol,2000,115(6):1041-1046.
[31]Ali S M,Chee S K,Yuen G Y,et al.Photodynamic therapy induced Fas-mediated apoptosis in human carcinoma cells.[J].Int J Mol Med,2002,9(3):257-270.
[32]Newmeyer D D,Ferguson-Miller S.Mitochondria:releasing power for life and unleashing the machineries of death.[J].Cell,2003,112(4):481-490.
[33]Tan K H,Hunziker W.Compartmentalization of Fas and Fas ligand may prevent auto- or paracrine apoptosis in epithelial cells.[J].Exp Cell Res,2003,284(2):283-290.
[34]Teiten M H,Marchal S,D H M,et al.Primary photodamage sites and mitochondrial events after Foscan photosensitization of MCF-7 human breast cancer cells.[J].Photochem Photobiol,2003,78(1):9-14.
[35]Inanami O,Yoshito A,Takahashi K,et al.Effects of BAPTA-AM and forskolin on apoptosis and cytochrome c release in photosensitized Chinese hamster V79 cells.[J].Photochem Photobiol,1999,70(4):650-655.
[36]Vantieghem A,Assefa Z,Vandenabeele P,et al.Hypericin-induced photosensitization of HeLa cells leads to apoptosis or necrosis.Involvement of cytochrome c and procaspase-3 activation in the mechanism of apoptosis.[J].FEBS Lett,1998,440(1-2):19-24.
[37]Vantieghem A,Xu Y,Declercq W,et al.Different pathways mediate cytochrome c release after photodynamic therapy with hypericin.[J].Photochem Photobiol,2001,74(2):133-142.
[38]张庆慧,李延忠,刘景琴,等.喉癌细胞增殖活性与组织学恶性度及预后关系的研究.[J].中华耳鼻咽喉科杂志,1995,30(2):305-307.
[1]LIPSON R L,BALDES E J,OLSEN A M.The use of a derivative of hematoporhyrin in tumor detection.[J].J Natl Cancer Inst,1961,26:1-11.
[2]Gregorie H B,Horger E O,Ward J L,et al.Hematoporphyrin-derivative fluorescence in malignant neoplasms.[J].Ann Surg,1968,167(6):820-828.
[3]Diamond I,Granelli S G,McDonagh A F,et al.Photodynamic therapy of malignant tumours.[J].Lancet,1972,2(7788):1175-1177.
[4]Kelly J F,Snell M E.Hematoporphyrin derivative:a possible aid in the diagnosis and therapy of carcinoma of the bladder.[J].J Urol,1976,115(2):150-151.
[5]Dougherty T J.Studies on the structure of porphyrins contained in Photofrin Ⅱ.[J].Photochem Photobiol,1987,46(5):569-573.
[6]Dougherty T J.Photodynamic therapy—new approaches.[J].Semin Surg Oncol,1989,5(1):6-16.
[7]Kato H.[History of photodynamic therapy—past,present and future][J].Gan To Kagaku Ryoho,1996,23(1):8-15.
[8]Dougherty T J.Photodynamic therapy.[J].Photochem Photobiol,1993,58(6):895-900.
[9]Athar M,Elmets C A,Bickers D R,et al.A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization.Activation of the xanthine oxidase pathway.[J].J Clin Invest,1989,83(4):1137-1143.
[10]Dougherty T J,Kaufman J E,Goldfarb A,et al.Photoradiation therapy for the treatment of malignant tumors.[J].Cancer Res,1978,38(8):2628- 2635.
[11] Bugelski P J, Porter C W, Dougherty T J. Autoradiographic distribution of hematoporphyrin derivative in normal and tumor tissue of the mouse.[J]. Cancer Res, 1981, 41(11 Pt 1): 4606-4612.
[12] Kessel D, Thompson P, Musselman B, et al. Chemistry of hematoporphyrin-derived photosensitizers.[J]. Photochem Photobiol, 1987, 46(5): 563-568.
[13] Peng Q, Warloe T, Berg K, et al. 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges.[J]. Cancer, 1997, 79(12): 2282-2308.
[14] Copper M P, Tan I B, Oppelaar H, et al. Meta- tetra(hydroxyphenyl) Chlorin photodynamic therapy in early-stage squamous cell carcinoma of the head and neck.[J]. Arch Otolaryngol Head Neck Surg, 2003, 129(7): 709-711.
[15] Diwu Z J, Haugland R P, Liu J, et al. Photosensitization by anticancer agents 21: new perylene- and aminonaphthoquinones.[J]. Free Radic Biol Med, 1996, 20(4): 589-593.
[16] Miller G G, Brown K, Ballangrud A M, et al. Preclinical assessment of hypocrellin B and hypocrellin B derivatives as sensitizers for photodynamic therapy of cancer: progress update. [J]. Photochem Photobiol, 1997, 65(4): 714-722.
[17] Zhang J, Cao E H, Li J F, et al. Photodynamic effects of hypocrellin A on three human malignant cell lines by inducing apoptotic cell death.[J]. J Photochem Photobiol B, 1998,43(2): 106-111.
[18] Estey E P, Brown K, Diwu Z, et al. Hypocrellins as photosensitizers for photodynamic therapy: a screening evaluation and pharmacokinetic study.[J]. Cancer Chemother Pharmacol, 1996, 37(4): 343-350.
[19] Hudson J B, Zhou J, Chen J, et al. Hypocrellin, from Hypocrella bambuase, is phototoxic to human immunodeficiency virus.[J]. Photochem Photobiol, 1994, 60(3): 253-255.
[20] Hudson J B, Imperial V, Haugland R P, et al. Antiviral activities of photoactive perylenequinones.[J]. Photochem Photobiol, 1997, 65(2): 352-354.
[21] van B H. On the evolution of some endoscopic light delivery systems for photodynamic therapy.[J]. Endoscopy, 1998, 30(4): 392-407.
[22] Rhodes L E, de R M, Enstrom Y, et al. Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial.[J]. Arch Dermatol, 2004, 140(1): 17-23.
[23] Taub A F. Photodynamic therapy in dermatology: history and horizons.[J]. J Drugs Dermatol, 2004, 3(1 Suppl): 8-25.
[24] Fijan S, Honigsmann H, Ortel B. Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine.[J]. Br J Dermatol, 1995, 133(2): 282-288.
[25] Morton C A, Whitehurst C, Moseley H, et al. Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen's disease.[J]. Br J Dermatol, 1996, 135(5): 766-771.
[26] Zeitouni N C, Shieh S, Oseroff A R. Laser and photodynamic therapy in the management of cutaneous malignancies.[J]. Clin Dermatol, 2001, 19(3): 328-338.
[27] Baas P, Saarnak A E, Oppelaar H, et al. Photodynamic therapy with meta-tetrahydroxyphenylchlorin for basal cell carcinoma: a phase I/II study.[J]. Br J Dermatol, 2001,145(1): 75-78.
[28] Triesscheijn M, Ruevekamp M, Antonini N, et al. Optimizing meso-tetra- hydroxyphenyl-chlorin-mediated photodynamic therapy for basal cell carcinoma.[J]. Photochem Photobiol, 2006, 82(6): 1686-1690.
[29] Sihvo E I, Luostarinen M E, Salo J A. Fate of patients with adenocarcinoma of the esophagus and the esophagogastric junction: a population-based analysis.[J]. Am J Gastroenterol, 2004, 99(3): 419-424.
[30] McCaughan J S, Hicks W, Laufman L, et al. Palliation of esophageal malignancy with photoradiation therapy.[J]. Cancer, 1984, 54(12): 2905-2910.
[31] Moghissi K, Dixon K, Thorpe J A, et al. The role of photodynamic therapy (PDT) in inoperable oesophageal cancer.[J]. Eur J Cardiothorac Surg, 2000, 17(2): 95-100.
[32] Okunaka T, Kato H, Conaka C, et al. Photodynamic therapy of esophageal carcinoma.[J]. Surg Endosc, 1990,4(3): 150-153.
[33] Sibille A, Lambert R, Souquet J C, et al. Long-term survival after photodynamic therapy for esophageal cancer.[J]. Gastroenterology, 1995, 108(2): 337-344.
[34] Grosjean P, Savary J F, Mizeret J, et al. Photodynamic therapy for cancer of the upper aerodigestive tract using tetra(m-hydroxyphenyl)chlorin.[J]. J Clin Laser Med Surg, 1996, 14(5): 281-287.
[35] Schweitzer V G, Bologna S, Batra S K. Photodynamic therapy for treatment of esophageal cancer: a preliminary report.[J]. Laryngoscope, 1993,103(6): 699-703.
[36] Overholt B F, Panjehpour M, DeNovo R C, et al. Photodynamic therapy for esophageal cancer using a 180 degrees windowed esophageal balloon.[J]. Lasers Surg Med, 1994,14(1): 27-33.
[37] Overholt B F, Lightdale C J, Wang K K, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international,partially blinded,randomized phase Ⅲ trial.[J].Gastrointest Endosc,2005,62(4):488-498.
[38]Pacifico R J,Wang K K,Wongkeesong L M,et al.Combined endoscopic mucosal resection and photodynamic therapy versus esophagectomy for management of early adenocarcinoma in Barrett's esophagus.[J].Clin Gastroenterol Hepatol,2003,1(4):252-257.
[39]Overholt B F,Panjehpour M,Haydek J M.Photodynamic therapy for Barrett's esophagus:follow-up in 100 patients.[J].Gastrointest Endosc,1999,49(1):1-7.
[40]Overholt B F,Panjehpour M,Halberg D L.Photodynamic therapy for Barrett's esophagus with dysplasia and/or early stage carcinoma:long-term results.[J].Gastrointest Endosc,2003,58(2):183-188.
[41]Gossner L,Stolte M,Sroka R,et al.Photodynamic ablation of high-grade dysplasia and early cancer in Barrett's esophagus by means of 5-aminolevulinic acid.[J].Gastroenterology,1998,114(3):448-455.
[42]Ortner M A,Zumbusch K,Liebetruth J,et al.Is topical delta- aminolevulinic acid adequate for photodynamic therapy in Barrett's esophagus? A pilot study.[J].Endoscopy,2002,34(8):611-616.
[43]McCaughan J S,Williams T E.Photodynamic therapy for endobronchial malignant disease:a prospective fourteen-year study.[J].J Thorac Cardiovasc Surg,1997,114(6):940-69467.
[44]Kato H.Photodynamic therapy for lung cancer—a review of 19 years'experience.[J].J Photochem Photobiol B,1998,42(2):96-99.
[45]Diaz-Jimenez J P,Martinez-Ballarin J E,Llunell A,et al.Efficacy and safety of photodynamic therapy versus Nd-YAG laser resection in NSCLC with airway obstruction.[J].Eur Respir J,1999,14(4):800-805.
[46]Moghissi K,Dixon K,Stringer M,et al.The place of bronchoscopic photodynamic therapy in advanced unresectable lung cancer: experience of 100 cases.[J]. Eur J Cardiothorac Surg, 1999, 15(1): 1-6.
[47] Furuse K, Fukuoka M, Kato H, et al. A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan Lung Cancer Photodynamic Therapy Study Group.[J]. J Clin Oncol, 1993, 11(10): 1852-1857.
[48] Imamura S, Kusunoki Y, Takifuji N, et al. Photodynamic therapy and/or external beam radiation therapy for roentgenologically occult lung cancer.[J]. Cancer, 1994, 73(6): 1608-1614.
[49] Ross P J, Grecula J, Bekaii-Saab T, et al. Incorporation of photodynamic therapy as an induction modality in non-small cell lung cancer.[J]. Lasers Surg Med, 2006, 38(10): 881-889.
[50] Baas P, van G I, Oppelaar H, et al. Enhancement of photodynamic therapy by mitomycin C: a preclinical and clinical study.[J]. Br J Cancer, 1996, 73(8): 945-951.
[51] Zoetmulder F A, van D J. Chest wall resection in the treatment of local recurrence of breast cancer.[J]. Eur J Surg Oncol, 1988, 14(2): 127—132.
[52] Hathaway C L, Rand R P, Moe R, et al. Salvage surgery for locally advanced and locally recurrent breast cancer.[J]. Arch Surg, 1994, 129(6): 582-587.
[53] Schuh M, Nseyo U O, Potter W R, et al. Photodynamic therapy for palliation of locally recurrent breast carcinoma.[J]. J Clin Oncol, 1987, 5(11): 1766-1770.
[54] Mang T S, Allison R, Hewson G, et al. A phase II/III clinical study of tin ethyl etiopurpurin (Purlytin)-induced photodynamic therapy for the treatment of recurrent cutaneous metastatic breast cancer.[J]. Cancer J Sci Am, 1998, 4(6): 378-384.
[55] Cairnduff F, Stringer M R, Hudson E J, et al. Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer.[J]. Br J Cancer, 1994, 69(3): 605-608.
[56] Baas P, van G I, Oppelaar H, et al. Enhancement of photodynamic therapy by mitomycin C: a preclinical and clinical study.[J]. Br J Cancer, 1996, 73(8): 945-951.
[57] Allison R R, Mang T S, Wilson B D. Photodynamic therapy for the treatment of nonmelanomatous cutaneous malignancies.[J]. Semin Cutan Med Surg, 1998, 17(2): 153-163.
[58] Gahlen J, Prosst R L, Stern J. [Photodynamic therapy in the gastrointestinal tract. Possibilities and limits][J]. Chirurg, 2002, 73(2): 122-131.
[59] Mimura S, Ito Y, Nagayo T, et al. Cooperative clinical trial of photodynamic therapy with photofrin II and excimer dye laser for early gastric cancer.[J]. Lasers Surg Med, 1996, 19(2): 168-172.
[60] Karanov S, Shopova M, Getov H. Photodynamic therapy in gastrointestinal cancer.[J]. Lasers Surg Med, 1991, 11(5): 395-398.
[61] Mimura S, Narahara H, Uehara H, et al. [Photodynamic therapy for gastric cancer][J]. Gan To Kagaku Ryoho, 1996,23(1): 41-46.
[62] Ell C, Gossner L, Hahn E G, et al. [Photodynamic therapy of a gastric stump carcinoma with curative intent. The first case report of a clinical application in Germany][J]. Dtsch Med Wochenschr, 1994,119(27): 951-955.
[63] Patrice T, Foultier M T, Yactayo S, et al. Endoscopic photodynamic therapy with haematoporphyrin derivative in gastroenterology.[J]. J Photochem Photobiol B, 1990,6(1-2): 157-165.
[64] Kelly J F, Snell M E, Berenbaum M C. Photodynamic destruction of human bladder carcinoma.[J]. Br J Cancer, 1975, 31(2): 237-244.
[65] Morales A. Treatment of superficial bladder cancer.[J]. Can Med Assoc J, 1980,122(10):1133-1138.
[66]Dougherty T J.Photodynamic therapy(PDT)of malignant tumors.[J].Crit Rev Oncol Hematol,1984,2(2):83-116.
[67]Rosenberg S J,Williams R D.Photodynamic therapy of bladder carcinoma.[J].Urol Clin North Am,1986,13(3):435-444.
[68]Benson R C.Laser photodynamic therapy for bladder cancer.[J].Mayo Clin Proc,1986,61(11):859-864.
[69]Nseyo U O,Dougherty T J,Boyle D G,et al.Whole bladder photodynamic therapy for transitional cell carcinoma of bladder.[J].Urology,1985,26(3):274-280.
[70]Berger A P,Steiner H,Stenzl A,et al.Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer:a single-center study.[J].Urology,2003,61(2):338-341.
[71]Nseyo U O,DeHaven J,Dougherty T J,et al.Photodynamic therapy(PDT)in the treatment of patients with resistant superficial bladder cancer:a long-term experience.[J].J Clin Laser Med Surg,1998,16(1):61-68.
[72]Kriegmair M,Baumgartner R,Lumper W,et al.Early clinical experience with 5-aminolevulinic acid for the photodynamic therapy of superficial bladder cancer.[J].Br J Urol,1996,77(5):667-671.
[73]Skyrme R J,French A J,Datta S N,et al.A phase-1 study of sequential mitomycin C and 5-aminolaevulinic acid-mediated photodynamic therapy in recurrent superficial bladder carcinoma.[J].BJU Int,2005,95(9):1206-1210.
[74]Pomer S,Grashev G,Sinn H,et al.Laser-induced fluorescence diagnosis and photodynamic therapy of human renal cell carcinoma.[J].Urol Int,1995,55(4):197-201.
[75]Popken G,Wetterauer U,Schultze-Seemann W.Kidney-preserving tumour resection in renal cell carcinoma with photodynamic detection by 5-aminolaevulinic acid:preclinical and preliminary clinical results.[J].BJU Int,1999,83(6):578-582.
[76]Ahn W S,Bae S M,Huh S W,et al.Necrosis-like death with plasma membrane damage against cervical cancer cells by photodynamic therapy.[J].Int J Gynecol Cancer,2004,14(3):475-482.
[77]Keefe K A,Chahine E B,DiSaia P J,et al.Fluorescence detection of cervical intraepithelial neoplasia for photodynamic therapy with the topical agents 5-aminolevulinic acid and benzoporphyrin-derivative monoacid ring.[J].Am J Obstet Gynecol,2001,184(6):1164-1169.
[78]Barnett A A,Haller J C,Cairnduff F,et al.A randomised,double-blind,placebo-controlled trial of photodynamic therapy using 5-aminolaevulinic acid for the treatment of cervical intraepithelial neoplasia.[J].Int J Cancer,2003,103(6):829-832.
[79]Copper M P,Tan I B,Oppelaar H,et al.Meta-tetra(hydroxyphenyl)chlorin photodynamic therapy in early-stage squamous cell carcinoma of the head and neck.[J].Arch Otolaryngol Head Neck Surg,2003,129(7):709-711.
[80]Hopper C,Kubler A,Lewis H,et al.mTHPC-mediated photodynamic therapy for early oral squamous cell carcinoma.[J].Int J Cancer,2004,111(1):138-146.
[81]Schuller D E,McCaughan J S,Rock R P.Photodynamic therapy in head and neck cancer.[J].Arch Otolaryngol,1985,111(6):351-355.
[82]Photoradiation therapy of head and neck cancer.[J].1984,170:681-691.
[83]Kubler A C,de C J,Hopper C,et al.Treatment of squamous cell carcinoma of the lip using Foscan-mediated photodynamic therapy.[J].Int J Oral Maxillofac Surg,2001,30(6):504-509.
[84]Keller G S,Doiron D R,Fisher G U.Photodynamic therapy in otolaryngology—head and neck surgery.[J].Arch Otolaryngol,1985,111(11):758-761.
[85]Lofgren L A,Hallgren S,Nilsson E,et al.Photodynamic therapy for recurrent nasopharyngeal cancer.[J].Arch Otolaryngol Head Neck Surg,1995,121(9):997-1002.
[86]Feyh J,Goetz A,Muller W,et al.Photodynamic therapy in head and neck surgery.[J].J Photochem Photobiol B,1990,7(2-4):353-358.
[87]Gluckman E,Roudet C,Hirsch I,et al.Prophylaxis of bacterial infections after bone marrow transplantation.A randomized prospective study comparing oral broad-spectrum nonabsorbable antibiotics(vancomycintobramycin-colistin)to absorbable antibiotics(ofloxacin-amoxicillin).[J].Chemotherapy,1991,37 Suppl 1:33-38.
[88]Kubler A C,de C J,Hopper C,et al.Treatment of squamous cell carcinoma of the lip using Foscan-mediated photodynamic therapy.[J].Int J Oral Maxillofac Surg,2001,30(6):504-509.
[89]Snyder J W,Greco W R,Bellnier D A,et al.Photodynamic therapy:a means to enhanced drug delivery to tumors.[J].Cancer Res,2003,63(23):8126-8131.
[90]Kirveliene V,Grazeliene G,Dabkeviciene D,et al.Schedule-dependent interaction between Doxorubicin and mTHPC-mediated photodynamic therapy in murine hepatoma in vitro and in vivo.[J].Cancer Chemother Pharmacol,2006,57(1):65-72.
[91]Chen B,Ahmed B,Landuyt W,et al.Potentiation of photodynamic therapy with hypericin by mitomycin C in the radiation-induced fibrosarcoma-1mouse tumor model.[J].Photochem Photobiol,2003,78(3):278-282.
[92]Gollnick S O,Vaughan L,Henderson B W.Generation of effective antitumor vaccines using photodynamic therapy.[J]. Cancer Res, 2002, 62(6): 1604-1608.
[93] Jalili A, Makowski M, Switaj T, et al. Effective photoimmunotherapy of murine colon carcinoma induced by the combination of photodynamic therapy and dendritic cells.[J]. Clin Cancer Res, 2004, 10(13): 4498-4508.
[94] Korbelik M, Sun J. Photodynamic therapy-generated vaccine for cancer therapy.[J]. Cancer Immunol Immunother, 2006, 55(8): 900-909.
[95] Dimitroff C J, Klohs W, Sharma A, et al. Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: implications for combination treatment with photodynamic therapy.[J]. Invest New Drugs, 1999,17(2): 121-135.
[96] Zhou Q, Olivo M, Lye K Y, et al. Enhancing the therapeutic responsiveness of photodynamic therapy with the antiangiogenic agents SU5416 and SU6668 in murine nasopharyngeal carcinoma models.[J]. Cancer Chemother Pharmacol, 2005, 56(6): 569-577.
[97] Ferrario A, Fisher A M, Rucker N, et al. Celecoxib and NS-398 enhance photodynamic therapy by increasing in vitro apoptosis and decreasing in vivo inflammatory and angiogenic factors.[J]. Cancer Res, 2005, 65(20): 9473-9478.
[98] Ferrario A, Gomer C J. Avastin enhances photodynamic therapy treatment of Kaposi's sarcoma in a mouse tumor model.[J]. J Environ Pathol Toxicol Oncol, 2006, 25(1-2): 251-259.
[99] El-Mofy A.M. Vitiligo and Psoralens. - Oxford: Pergamon Press, 1968. -147
[100] Wyss P. History of Photomedicine // Wyss P., Tadir Y., Tromberg B.J., Haller U. (eds): Photomedicine in Gynecology and Reproduction. - Basel: Karger, 2000. 4-11.
[101]Fahmy I.R.,Abu-Shady H.:Ammi majus linn:The isolation and properties of ammoidin,ammidin and majudin,and their effect in the treatment of leukoderma.[J]J.Pharm.Pharmacol.- 1948.21:499-503.
[102]Abels C.,Goetz A.E.A clinical protocol for photodynamic therapy//H.Honigsmann,G.Jori,A.R.Young(eds):The Fundamental Bases of Phototherapy.OEMF spa- Milano,1996.265-284.
[103]Rasmussen D.S.Ward G.E.Figge F.H.J.Fluorescence of human lymphatic and cancer tissues following high doses of intravenous hematoporphyrin [J]Cancer.1955.1:78-81.
[104]Tappeiner H.JesionekH.Therapeutische Versuche mit fluoreszierenden Stoffen[J]Munch.Med.Wschr.1903.50:2042-2044.
[105]Jesionek H.,Yappeiner H.Zur Behandlung der Hautcarcinome mit fluoreszierenden Stoffen[J]Dtsch.Arch.Klin.Med.1905.82:223-226.
[106]Tappeiner H.,Jodlbauer A.Uber die Wirkung der photodynamischen (fluoreszierenden)Stoffen auf Protozoen und Enzyme.[J].Dtsch.Arch.Klin.Med,1904,80:427-437.
[107]Hausmann W.H.Die sensibilisierende Wirkung des Hamatoporphyrins.[J].Biochem Z.1910.30:276-316.
[108]Hausmann W.H.Die sensibilisierende Wirkung tierischer Farbstoffe und ihre physiologische Bedeutung.[J].Wien.Klin.Wochenschr.1908.21:1527-1529.
[109]Meyer-Betz F.Untersuchung uber die biologische(photodynamische)Wirkung des Hamatoporphyrins und anderer Derivate des Blut- und Gallenfarbstoffs.[J].Dtsch.Arch.Klin.Med.- 1913.112:476-503.
[110]Policard A.Etudes sur les aspects offerts par des tumeurs experimentales examines a la lumiere de Wood.[J].CR Soc.Biol.1924.91:1423-1424.
[111]Lipson R.L.,Gray M.J.,Baldes E.J.Hematoporphyrin derivative for detection and management of cancer/Proc.9-th International Cancer Congress.- Tokyo,Japan,1966.- 393 p.
[112]Figge F.H.J.,Weiland G.S.,Manganiello O.J.Cancer detection and therapy.Affinity of neoplastic,embryonic,and traumatized tissues for porphyrins and metalloporphyrins.[J]Proc.Soc.Exp.Biol.Med.1948.68:640-641.
[113]Schwartz S.,Absolon K.,Vermund H.Some relationships of porphyrins,X-rays and tumors.[J].Bull.Minn.Univ.School Med.1955.27:7-13.
[114]丁新民.顾瑛.刘凡光等.光动力学治疗肿瘤患者3878例情况分析及近12年临床文献复习。[J].中国临床康复.2004,8(11):2014-2015.
[115]赵开弘.蒋丽金.竹红菌甲素在碱性和中性溶液中的结构变化.[J].有机化学,1989,9(3):252-254
[116]许娜飞.李景福.曹恩华等.Hela细胞对竹红菌甲素摄取的直接观察与动态过程分析.[J].生物物理学报.1995.11(2):261-266
[117]许娜飞.曹恩华.李景福.竹红菌甲素(HA)光敏致突变作用的研究。[J].生物物理学报,1995,11(4):604-608
[118]曹恩华.许娜飞.张健等.膜脂质过氧化物在光敏诱发细胞突变中的作用.[J1].激光生物学报.1998,7(1):3-7
[119]秦云才.韩东升.张伟等.光动力学疗效加放疗综合治疗食管癌的近期疗效分析[J].实用肿瘤学杂志,1997,11(12):109-111
[120]张景伟.王建华.刘法文等.食管癌放射治疗加光动力疗法长期生存分析[J].中国医师杂志,2003,5(8):1058-1060.
[121]雷银雪.食管不典型增生和早期癌的光动力学治疗[J].德国医学,1998,2(15):90
[122]陈广幸.李章生.汪森明等.光动力治疗中晚期中央型肺癌的临床初探.肿瘤防治杂志,2005,12(23):1798-1799.
[123]曾超英.杨栋.陈骥等.B超引导经皮介入光动力治疗中晚期肝癌30 例.[J].中国激光医学杂志,1996,5:63-66.
[124]曾超英.杨栋.黄萍等.光动力治疗肝癌远期疗效及影响因素探讨[J].中国激光医学杂志,2000,9:146-150.
[125]曾超英.黄萍.杨栋等.光动力作用对活体肝组织损伤研究[J].中国激光医学杂志,2000,9:141-145.
[126]陈静.王彩霞.宛苏等.CT引导下光动力学疗法治疗原发性肝癌的研究.[J].中华实验外科杂志,1994,11(6):341-2.
[127]汪连兴.陈拯民.瞿法康等.光动力学治疗中晚期大肠癌(附35例报告).[J].激光医学,1992,2(5):22-5.[
128]孙振权.罗国仪.光动力学治疗鼻咽癌57例分析.[J].中华肿瘤杂志,1990,12(2):120-121
[129]孙振权.罗国仪.激光光动力学治疗复发性鼻咽癌的研究 附191例分析.[J].中国激光医学杂志,1996,5(3):134
[130]卢明.黄鸿年.绦博.血卟啉分离物(HPS)放射增敏效应的实验研究.[J].中国肿瘤临床,1987,14:341
[131]胡德恩.林祥松.王晓风放射治疗鼻咽癌患者免疫状态的影响.[J].肿瘤防治研究,1987,14:21
[132]粱亚云.王耐勤.于刚.光敏剂一血卟啉衍生物(HPD)对小鼠免疫功能的影响.[J].上海免疫学杂志.1985,45-79
[133]陆明芳.光动力学疗法试治放疗后复发性鼻咽癌.[J].中国激光医学杂志.2000,9(3):164-165
[134]漆其光.廖卫国.温清泉等.激光动力学治疗早期喉癌的临床分析.[J].广东医学,2005,26(7):962-963.
[135]江新.激光和光动力学治疗复发性鼻窦癌.[J].应用激光.1992,12(5):237-238.
[136]阮珊真.盛月霞.光敏疗法治疗颈淋巴结转移癌2例报道.[J].肿瘤.1989,9:216-216.
[2]Henderson B W,Dougherty T J.How does photodynamic therapy work?[J].Photochem Photobiol,1992,55(1):145-157.
[3]Zumbraegel A,Bichler K H,Krause F S,et al.The photodynamic diagnosis(PDD)for early detection of carcinoma and dysplasia of the bladder.[J].Adv Exp Med Biol,2003,539(Pt A):61-66.
[4]Athar M,Elmets C A,Bickers D R,et al.A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization.Activation of the xanthine oxidase pathway.[J].J Clin Invest,1989,83(4):1137-1143.
[5]Rittenhouse-Diakun K,Van L H,Morgan J,et al.The role of transferrin receptor(CD71)in photodynamic therapy of activated and malignant lymphocytes using the heme precursor delta-aminolevulinic acid(ALA).[J].Photochem Photobiol,1995,61(5):523-528.
[6]Peng Q,Warloe T,Berg K,et al.5-Aminolevulinic acid-based photodynamic therapy.Clinical research and future challenges.[J].Cancer,1997,79(12):2282-2308.
[7]Ratcliffe S L,Matthews E K.Modification of the photodynamic action of delta-aminolaevulinic acid(ALA)on rat pancreatoma cells by mitochondrial benzodiazepine receptor ligands.[J].Br J Cancer,1995,71(2):300-305.
[8]Iinuma S,Farshi S S,Ortel B,et al.A mechanistic study of cellular photodestruction with 5-aminolaevulinic acid-induced porphyrin.[J].Br J Cancer,1994,70(1):21-28.
[9]Manivasager V,Heng P W,Hao J,et al.A study of 5-aminolevulinic acid and its methyl ester used in in vitro and in vivo systems of human bladder cancer.[J].Int J Oncol,2003,22(2):313-318.
[1]Grosjean P,Savary J F,Mizeret J,et al.Photodynamic therapy for cancer of the upper aerodigestive tract using tetra(m-hydroxyphenyl)chlorin.[J].J Clin Laser Med Surg,1996,14(5):281-287.
[2]Maier A,Yomaselli F,Matzi V,et al.Photosensitization with hematoporphyrin derivative compared to 5-aminolaevulinic acid for photodynamic therapy of esophageal carcinoma.[J].Ann Thorac Surg,2001,72(4):1136-1140.
[3]Mimura S,Narahara H,Uehara H,et al.[Photodynamic therapy for gastric cancer][J].Gan To Kagaku Ryoho,1996,23(1):41-46.
[4]Wierrani F,Kubin A,Jindra R,et al.5-aminolevulinic acid-mediated photodynamic therapy of intraepithelial neoplasia and human papillomavirus of the uterine cervix—a new experimental approach.[J].Cancer Detect Prey,1999,23(4):351-355.
[5]Blume J E,Oseroff A R.Aminolevulinic acid photodynamic therapy for skin cancers.[J].Dermatol Clin,2007,25(1):5-14.
[6]Braathen L R,Szeimies R M,Basset-Seguin N,et al.Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer:an international consensus.International Society for Photodynamic Therapy in Dermatology,2005.[J].J Am Acad Dennatol,2007,56(1):125-143.
[7]Henderson B W,Busch T M,Vaughan L A,et al.Photofrin photodynamic therapy can significantly deplete or preserve oxygenation in human basal cell carcinomas during treatment,depending on fluence rate.[J].Cancer Res,2000,60(3):525-529.
[8]Rittenhouse-Diakun K,Van L H,Morgan J,et al.The role of transferrin receptor(CD71)in photodynamic therapy of activated and malignant lymphocytes using the heme precursor delta-aminolevulinic acid (ALA).[J].Photochem Photobiol,1995,61(5):523-528.
[9]Peng Q,Warloe T,Berg K,et al.5-Aminolevulinic acid-based photodynamic therapy.Clinical research and future challenges.[J].Cancer,1997,79(12):2282-2308.
[10]Manivasager V,Heng P W,Hao J,et al.A study of 5-aminolevulinic acid and its methyl ester used in in vitro and in vivo systems of human bladder cancer.[J].Int J Oncol,2003,22(2):313-318.
[11]Wu S M,Ren Q G,Zhou M O,et al.Protoporphyrin Ⅸ production and its photodynamic effects on glioma cells,neuroblastoma cells and normal cerebellar granule cells in vitro with 5-aminolevulinic acid and its hexylester.[J].Cancer Lett,2003,200(2):123-131.
[12]Ren Q G,Wu S M,Peng Q,et al.Comparison of 5-aminolevulinic acid and its hexylester mediated photodynamic action on human hepatoma cells.[J].Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao(Shanghai),2002,34(5):650-654.
[13]Alexiades-Armenakas M.Aminolevulinic acid photodynamic therapy for actinic keratoses/actinic cheilitis/acne:vascular lasers.[J].Dermatol Clin,2007,25(1):25-33.
[14]Becker D M,Kramer S,Viljoen J D.Delta-aminolevulinic acid uptake by rabbit brain cerebral cortex.[J].J Neurochem,1974,23(5):1019-1023.
[15]Kessel D,Antolovich M,Smith K M.The role of the peripheral benzodiazepine receptor in the apoptotic response to photodynamic therapy.[J].Photochem Photobiol,2001,74(2):346-349.
[16]Brennan M J,Cantrill R C.Delta-aminolaevulinic acid is a potent agonist for GABA autoreceptors.[J].Nature,1979,280(5722):514-515.
[17]McLoughlin J L,Cantrill R C.The effect of delta-aminolaevulinic acid on the high affinity uptake of aspartic acid by rat brain synaptosomes.[J].Gen Pharmacol,1984,15(6):553-555.
[18]Cheeks C,Wedeen R P.Renal tubular transport of delta-aminolevulinic acid in rat.[J].Proc Soc Exp Biol Med,1986,181(4):596-601.
[19]Doring F,Walter J,Will J,et al.Delta-aminolevulinic acid transport by intestinal and renal peptide transporters and its physiological and clinical implications.[J].J Clin Invest,1998,101(12):2761-2767.
[20]Brennan M J,Cantrill R C.The effects of delta-aminolaevulinic acid on the uptake and efflux of amino acid neurotransmitters in rat brain synaptosomes.[J].J Neurochem,1979,33(3):721-725.
[21]Latkowski B,Gryczynski M,Murlewska A.[Use of sensitizers and photo laser for diagnosis and treatment of malignant tumors][J].Otolaryngol Pol,1995,49 Suppl 20:205-208.
[22]Henderson B W,Dougherty T J.How does photodynamic therapy work?[J].Photochem Photobiol,1992,55(1):145-157.
[23]刘慧龙、刘凡光,影响光动力疗法的几个主要因素.[J].中国激光医学杂志.2002,11(2):121-124
[24]张苏娟,张镇西,蒋大宗.基于氨乙酰(ALA)脂类衍生物的光动力疗法(PDT).[J].J Biomed Eng.2002,19(2):310-314。
[1]Bedwell J,MacRobert A J,Phillips D,et al.Fluorescence distribution and photodynamic effect of ALA-induced PP Ⅸ in the DMH rat colonic tumour model.[J].Br J Cancer,1992,65(6):818-824.
[2]Henderson B W,Vaughan L,Bellnier D A,et al.Photosensitization of murine tumor,vasculature and skin by 5-aminolevulinic acid-induced porphyrin.[J].Photochem Photobiol,1995,62(4):780-789.
[3]Loh C S,MacRobert A J,Bedwell J,et al.Oral versus intravenous administration of 5-aminolaevulinic acid for photodynamic therapy.[J].Br J Cancer,1993,68(1):41-51.
[4]Orenstein A,Kostenich G,Roitman L,et al.A comparative study of tissue distribution and photodynamic therapy selectivity of chlorin e6,Photofrin Ⅱand ALA-induced protoporphyrin Ⅸ in a colon carcinoma model.[J].Br J Cancer,1996,73(8):937-944.
[5]Xu S,Menon I A,Becker M A,et al.Endogenous porphyrins in murine skin and transplanted PAM-212 squamous cell carcinoma tissues after injection of delta-aminolevulinic acid.[J].Chin Med J(Engl),1995,108(4):286-290.
[6]Lofgren L A,Ronn A M,Nouri M,et al.Efficacy of intravenous delta-aminolaevulinic acid photodynamic therapy on rabbit papillomas.[J].Br J Cancer,1995,72(4):857-864.
[7]Regula J,Ravi B,Bedwell J,et al.Photodynamic therapy using 5-aminolaevulinic acid for experimental pancreatic cancer—prolonged animal survival.[J].Br J Cancer,1994,70(2):248-254.
[8]van H R,Hekking-Weijma J M,Wilson J H,et al.Adjuvant intraoperative photodynamic therapy diminishes the rate of local recurrence in a rat mammary tumour model.[J].Br J Cancer,1995,71(4):733-737.
[9]Lilge L,Olivo M C,Schatz S W,et al.The sensitivity of normal brain and intracranially implanted VX2 tumour to interstitial photodynamic therapy.[J].Br J Cancer,1996,73(3):332-343
[10]Abels C,Heil P,Dellian M,et al.In vivo kinetics and spectra of 5-aminolaevulinic acid-induced fluorescence in an amelanotic melanoma of the hamster.[J].Br J Cancer,1994,70(5):826-833
[11]Hermes-Lima M.How do Ca2+ and 5-aminolevulinic acid-derived oxyradicals promote injury to isolated mitochondria?[J].Free Radic Biol Med,1995,19(3):381-390.
[12]Bermudez M M,Correa G S,Chianelli M S,et al.Evidence that 4-aminobutyric acid and 5-aminolevulinic acid share a common transport system into Saccharomyces cerevisiae.[J].Int J Biochem Cell Biol,1995,27(2):169-173.
[13]Oteiza P I,Kleinman C G,Demasi M,et al.5-Aminolevulinic acid induces iron release from ferritin.[J].Arch Biochem Biophys,1995,316(1):607-611.
[14]Hermes-Lima M,Castilho R F,Valle V G,et al.Calcium-dependent mitochondrial oxidative damage promoted by 5-aminolevulinic acid.[J].Biochim Biophys Acta,1992,1180(2):201-206.
[15]Hermes-Lima M,Valle V G,Vercesi A E,et al.Damage to rat liver mitochondria promoted by delta-aminolevulinic acid-generated reactive oxygen species:connections with acute intermittent porphyria and lead-poisoning.[J].Biochim Biophys Acta,1991,1056(1):57-63.
[16]Sustained high plasma 5-aminolaevulinic acid concentration in a volunteer:no porphyric symptoms.[J].1992,22(6):407-411.
[17]van V N,de B H,Berg R J,et al.Kinetics and localisation of PpIX fluorescence after topical and systemic ALA application,observed in skin and skin tumours of UVB-treated mice.[J].Br J Cancer,1996,73(7):925-930.
[18]Peng Q,Warloe T,Moan J,et al.Distribution of 5-aminolevulinic acid-induced porphyrins in noduloulcerative basal cell carcinoma.[J].Photochem Photobiol,1995,62(5):906-913.
[19]Dolmans D E,Fukumura D,Jain R K.Photodynamic therapy for cancer.[J].Nat Rev Cancer,2003,3(5):380-387.
[20]Janda P,Sroka R,Baumgartner R,et al.Laser treatment of hyperplastic inferior nasal turbinates:a review.[J].Lasers Surg Med,2001,28(5):404-413.
[21]Chan W H,Yu J S,Yang S D.Apoptotic signalling cascade in photosensitized human epidermal carcinoma A431 cells:involvement of singlet oxygen,c-Jun N-terminal kinase,caspase-3 and p21-activated kinase 2.[J].Biochem J,2000,351(Pt 1):221-232.
[22]Zhuang S,Demirs J T,Kochevar I E.p38 mitogen-activated protein kinase mediates bid cleavage,mitochondrial dysfunction,and caspase-3activation during apoptosis induced by singlet oxygen but not by hydrogen peroxide.[J].J Biol Chem,2000,275(34):25939-25948.
[23]Grebenova D,Kuzelova K,Smetana K,et al.Mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by 5-aminolevulinic acid-based photodynamic therapy in HL60 leukemia cells.[J].J Photochem Photobiol B,2003,69(2):71-85.
[24]Karbownik M,Reiter R J.Melatonin protects against oxidative stress caused by delta-aminolevulinic acid:implications for cancer reduction.[J].Cancer Invest,2002,20(2):276-286.
[25]Henderson B W,Fingar V H.Oxygen limitation of direct tumor cell kill during photodynamic treatment of a murine tumor model.[J].Photochem Photobiol,1989,49(3):299-304.
[26]Canti G,Marelli O,Ricci L,et al.Haematoporphyrin-treated murine lymphocytes:in vitro inhibition of DNA synthesis and light-mediated inactivation of ceils responsible for GVHR.[J].Photochem Photobiol,1981,34(5):589-594.
[27]Korbelik M.Induction of tumor immunity by photodynamic therapy.[J].J Clin Laser Med Surg,1996,14(5):329-334.
[1] Schuitmaker J J, Baas P, van L H, et al. Photodynamic therapy: a promising new modality for the treatment of cancer.[J]. J Photochem Photobiol B, 1996, 34(1): 3-12.
[2] Ochsner M. Photophysical and photobiological processes in the photo- dynamic therapy of tumours. [J]. J Photochem Photobiol B, 1997,39(1): 1-18.
[3] Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.[J]. Cell, 1996, 86(3): 353—364.
[4] Klagsbrun M, Soker S. VEGF/VPF: the angiogenesis factor found?[J]. Curr Biol, 1993,3(10): 699-702.
[5] Dvorak H F, Brown L F, Detmar M, et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.[J]. Am JPathol, 1995,146(5): 1029-1039.
[6] Osiecka B J, Ziolkowski P, Gamian E, et al. Determination of vascular-endothelial growth factor levels in serum from tumor-bearing BALB/c mice treated with photodynamic therapy.[J]. Med Sci Monit, 2003,9(4): 110—114.
[7] Schmidt-Erfurth U, Schlotzer-Schrehard U, Cursiefen C, et al. Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor.[J]. Invest Ophthalmol Vis Sci, 2003, 44(10): 4473-4480.
[8] Solban N, Selbo P K, Sinha A K, et al. Mechanistic investigation and implications of photodynamic therapy induction of vascular endothelial growth factor in prostate cancer.[J]. Cancer Res, 2006, 66(11): 5633—5640.
[9] Zhang X, Jiang F, Zhang Z G, et al. Low-dose photodynamic therapy increases endothelial cell proliferation and VEGF expression in nude mice brain.[J]. Lasers Med Sci, 2005, 20(2): 74-79.
[10] Ferrario A, von T K, Rucker N, et al. Antiangiogenic treatment enhances photodynamic therapy responsiveness in a mouse mammary carcinoma. [J]. Cancer Res, 2000, 60(15): 4066-4069.
[11] Dimitroff C J, Klohs W, Sharma A, et al. Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: implications for combination treatment with photodynamic therapy.[J]. Invest New Drugs, 1999, 17(2): 121-135.
[12] Zhou Q, Olivo M, Lye K Y, et al. Enhancing the therapeutic responsiveness of photodynamic therapy with the antiangiogenic agents SU5416 and SU6668 in murine nasopharyngeal carcinoma models.[J]. Cancer Chemother Pharmacol, 2005, 56(6): 569-577.
[13] Abels C, Heil P, Dellian M, et al. In vivo kinetics and spectra of 5-aminolaevulinic acid-induced fluorescence in an amelanotic melanoma of the hamster.[J]. Br J Cancer, 1994, 70(5): 826-833.
[14] Martin A, Tope W D, Grevelink J M, et al. Lack of selectivity of protoporphyrin IX fluorescence for basal cell carcinoma after topical application of 5-aminolevulinic acid: implications for photodynamic treatment.[J]. Arch Dermatol Res, 1995, 287(7): 665—674.
[15] Miyachi K, Fritzler M J, Tan E M. Autoantibody to a nuclear antigen in proliferating cells.[J]. J Immunol, 1978, 121(6): 2228-2234.
[16] Ducoux M, Urbach S, Baldacci G, et al. Mediation of proliferating cell nuclear antigen (PCNA)-dependent DNA replication through a conserved p21(Cip1)-like PCNA-binding motif present in the third subunit of human DNA polymerase delta.[J].J Biol Chem,2001,276(52):49258-49266.
[17]Parrilla-Castellar E R,Arlander S J,Karnitz L.Dial 9-1-1 for DNA damage:the Rad9-Husl-Radl(9-1-1)clamp complex.[J].DNA Repair (Amst),2004,3(8-9):1009-1014.
[18]Friedrich-Heineken E,Toueille M,Yarmler B,et al.The two DNA clamps Rad9/Rad1/Hus1 complex and proliferating cell nuclear antigen differentially regulate flap endonuclease 1 activity.[J].J Mol Biol,2005,353(5):980-989.
[19]Skibbens R V,Corson L B,Koshland D,et al.Ctf7p is essential for sister chromatid cohesion and links mitotic chromosome structure to the DNA replication machinery.[J].Genes Dev,1999,13(3):307-319.
[20]Chuang L S,Ian H I,Koh T W,et al.Human DNA-(cytosine-5)methyltransferase-PCNA complex as a target for p21WAFI.[J].Science,1997,277(5334):1996-2000.
[21]Haupt S,Berger M,Goldberg Z,et al.Apoptosis - the p53 network.[J].J Cell Sci,2003,116(Pt 20):4077-4085.
[22]Lukomski M,Jozefowicz-Korczynska M,Kobos J.[The prognostic value of modified quantitative classification and expression of monoclonal antibodies against PCNA in laryngeal neoplasm(introduction)][J].Otolaryngol Pol,1995,49 Suppl 20:87-92.
[23]Golusinski W,Szmeja Z,Olofsson J,et al.[Diagnostic and prognostic value of p53 oncogene and the selected neoplastic markers(Ki67,PCNA,DNA ploidy)of the ultrastructure in patients with laryngeal cancer][J].Otolaryngol Pol,1996,50(6):607-617.
[24]Kram A,Domagala W.Proliferating cell nuclear antigen(PCNA) expression in laryngeal squamous cell carcinomas.An immuno- histochemical study.[J].Pol J Pathol,1996,47(4):183-187.
[25]Welkoborsky H J,Hinni M,Dienes H P,et al.Predicting recurrence and survival in patients with laryngeal cancer by means of DNA cytometry,tumor front grading,and proliferation markers.[J].Ann Otol Rhinol Laryngol,1995,104(7):503-510.
[26]Almeida R D,Gomes E R,Carvalho A P,et al.Calpains are activated by photodynamic therapy but do not contribute to apoptotic tumor cell death.[J].Cancer Lett,2004,216(2):183-189.
[27]Wallach D,Varfolomeev E E,Malinin N L,et al.Tumor necrosis factor receptor and Fas signaling mechanisms.[J].Annu Rev Immunol,1999,17:331-367.
[28]Apoptosomes:engines for caspase activation.[J].2002,14(6):715-720.
[29]Kim T H,Zhao Y,Barber M J,et al.Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax.[J].J Biol Chem,2000,275(50):39474-39481.
[30]Ahmad N,Gupta S,FeTes D K,et al.Involvement ofFas(APO-1/CD-95)during photodynamic-therapy-mediated apoptosis in human epidermoid carcinoma A431 cells.[J].J Invest Dermatol,2000,115(6):1041-1046.
[31]Ali S M,Chee S K,Yuen G Y,et al.Photodynamic therapy induced Fas-mediated apoptosis in human carcinoma cells.[J].Int J Mol Med,2002,9(3):257-270.
[32]Newmeyer D D,Ferguson-Miller S.Mitochondria:releasing power for life and unleashing the machineries of death.[J].Cell,2003,112(4):481-490.
[33]Tan K H,Hunziker W.Compartmentalization of Fas and Fas ligand may prevent auto- or paracrine apoptosis in epithelial cells.[J].Exp Cell Res,2003,284(2):283-290.
[34]Teiten M H,Marchal S,D H M,et al.Primary photodamage sites and mitochondrial events after Foscan photosensitization of MCF-7 human breast cancer cells.[J].Photochem Photobiol,2003,78(1):9-14.
[35]Inanami O,Yoshito A,Takahashi K,et al.Effects of BAPTA-AM and forskolin on apoptosis and cytochrome c release in photosensitized Chinese hamster V79 cells.[J].Photochem Photobiol,1999,70(4):650-655.
[36]Vantieghem A,Assefa Z,Vandenabeele P,et al.Hypericin-induced photosensitization of HeLa cells leads to apoptosis or necrosis.Involvement of cytochrome c and procaspase-3 activation in the mechanism of apoptosis.[J].FEBS Lett,1998,440(1-2):19-24.
[37]Vantieghem A,Xu Y,Declercq W,et al.Different pathways mediate cytochrome c release after photodynamic therapy with hypericin.[J].Photochem Photobiol,2001,74(2):133-142.
[38]张庆慧,李延忠,刘景琴,等.喉癌细胞增殖活性与组织学恶性度及预后关系的研究.[J].中华耳鼻咽喉科杂志,1995,30(2):305-307.
[1]LIPSON R L,BALDES E J,OLSEN A M.The use of a derivative of hematoporhyrin in tumor detection.[J].J Natl Cancer Inst,1961,26:1-11.
[2]Gregorie H B,Horger E O,Ward J L,et al.Hematoporphyrin-derivative fluorescence in malignant neoplasms.[J].Ann Surg,1968,167(6):820-828.
[3]Diamond I,Granelli S G,McDonagh A F,et al.Photodynamic therapy of malignant tumours.[J].Lancet,1972,2(7788):1175-1177.
[4]Kelly J F,Snell M E.Hematoporphyrin derivative:a possible aid in the diagnosis and therapy of carcinoma of the bladder.[J].J Urol,1976,115(2):150-151.
[5]Dougherty T J.Studies on the structure of porphyrins contained in Photofrin Ⅱ.[J].Photochem Photobiol,1987,46(5):569-573.
[6]Dougherty T J.Photodynamic therapy—new approaches.[J].Semin Surg Oncol,1989,5(1):6-16.
[7]Kato H.[History of photodynamic therapy—past,present and future][J].Gan To Kagaku Ryoho,1996,23(1):8-15.
[8]Dougherty T J.Photodynamic therapy.[J].Photochem Photobiol,1993,58(6):895-900.
[9]Athar M,Elmets C A,Bickers D R,et al.A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization.Activation of the xanthine oxidase pathway.[J].J Clin Invest,1989,83(4):1137-1143.
[10]Dougherty T J,Kaufman J E,Goldfarb A,et al.Photoradiation therapy for the treatment of malignant tumors.[J].Cancer Res,1978,38(8):2628- 2635.
[11] Bugelski P J, Porter C W, Dougherty T J. Autoradiographic distribution of hematoporphyrin derivative in normal and tumor tissue of the mouse.[J]. Cancer Res, 1981, 41(11 Pt 1): 4606-4612.
[12] Kessel D, Thompson P, Musselman B, et al. Chemistry of hematoporphyrin-derived photosensitizers.[J]. Photochem Photobiol, 1987, 46(5): 563-568.
[13] Peng Q, Warloe T, Berg K, et al. 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges.[J]. Cancer, 1997, 79(12): 2282-2308.
[14] Copper M P, Tan I B, Oppelaar H, et al. Meta- tetra(hydroxyphenyl) Chlorin photodynamic therapy in early-stage squamous cell carcinoma of the head and neck.[J]. Arch Otolaryngol Head Neck Surg, 2003, 129(7): 709-711.
[15] Diwu Z J, Haugland R P, Liu J, et al. Photosensitization by anticancer agents 21: new perylene- and aminonaphthoquinones.[J]. Free Radic Biol Med, 1996, 20(4): 589-593.
[16] Miller G G, Brown K, Ballangrud A M, et al. Preclinical assessment of hypocrellin B and hypocrellin B derivatives as sensitizers for photodynamic therapy of cancer: progress update. [J]. Photochem Photobiol, 1997, 65(4): 714-722.
[17] Zhang J, Cao E H, Li J F, et al. Photodynamic effects of hypocrellin A on three human malignant cell lines by inducing apoptotic cell death.[J]. J Photochem Photobiol B, 1998,43(2): 106-111.
[18] Estey E P, Brown K, Diwu Z, et al. Hypocrellins as photosensitizers for photodynamic therapy: a screening evaluation and pharmacokinetic study.[J]. Cancer Chemother Pharmacol, 1996, 37(4): 343-350.
[19] Hudson J B, Zhou J, Chen J, et al. Hypocrellin, from Hypocrella bambuase, is phototoxic to human immunodeficiency virus.[J]. Photochem Photobiol, 1994, 60(3): 253-255.
[20] Hudson J B, Imperial V, Haugland R P, et al. Antiviral activities of photoactive perylenequinones.[J]. Photochem Photobiol, 1997, 65(2): 352-354.
[21] van B H. On the evolution of some endoscopic light delivery systems for photodynamic therapy.[J]. Endoscopy, 1998, 30(4): 392-407.
[22] Rhodes L E, de R M, Enstrom Y, et al. Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial.[J]. Arch Dermatol, 2004, 140(1): 17-23.
[23] Taub A F. Photodynamic therapy in dermatology: history and horizons.[J]. J Drugs Dermatol, 2004, 3(1 Suppl): 8-25.
[24] Fijan S, Honigsmann H, Ortel B. Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine.[J]. Br J Dermatol, 1995, 133(2): 282-288.
[25] Morton C A, Whitehurst C, Moseley H, et al. Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen's disease.[J]. Br J Dermatol, 1996, 135(5): 766-771.
[26] Zeitouni N C, Shieh S, Oseroff A R. Laser and photodynamic therapy in the management of cutaneous malignancies.[J]. Clin Dermatol, 2001, 19(3): 328-338.
[27] Baas P, Saarnak A E, Oppelaar H, et al. Photodynamic therapy with meta-tetrahydroxyphenylchlorin for basal cell carcinoma: a phase I/II study.[J]. Br J Dermatol, 2001,145(1): 75-78.
[28] Triesscheijn M, Ruevekamp M, Antonini N, et al. Optimizing meso-tetra- hydroxyphenyl-chlorin-mediated photodynamic therapy for basal cell carcinoma.[J]. Photochem Photobiol, 2006, 82(6): 1686-1690.
[29] Sihvo E I, Luostarinen M E, Salo J A. Fate of patients with adenocarcinoma of the esophagus and the esophagogastric junction: a population-based analysis.[J]. Am J Gastroenterol, 2004, 99(3): 419-424.
[30] McCaughan J S, Hicks W, Laufman L, et al. Palliation of esophageal malignancy with photoradiation therapy.[J]. Cancer, 1984, 54(12): 2905-2910.
[31] Moghissi K, Dixon K, Thorpe J A, et al. The role of photodynamic therapy (PDT) in inoperable oesophageal cancer.[J]. Eur J Cardiothorac Surg, 2000, 17(2): 95-100.
[32] Okunaka T, Kato H, Conaka C, et al. Photodynamic therapy of esophageal carcinoma.[J]. Surg Endosc, 1990,4(3): 150-153.
[33] Sibille A, Lambert R, Souquet J C, et al. Long-term survival after photodynamic therapy for esophageal cancer.[J]. Gastroenterology, 1995, 108(2): 337-344.
[34] Grosjean P, Savary J F, Mizeret J, et al. Photodynamic therapy for cancer of the upper aerodigestive tract using tetra(m-hydroxyphenyl)chlorin.[J]. J Clin Laser Med Surg, 1996, 14(5): 281-287.
[35] Schweitzer V G, Bologna S, Batra S K. Photodynamic therapy for treatment of esophageal cancer: a preliminary report.[J]. Laryngoscope, 1993,103(6): 699-703.
[36] Overholt B F, Panjehpour M, DeNovo R C, et al. Photodynamic therapy for esophageal cancer using a 180 degrees windowed esophageal balloon.[J]. Lasers Surg Med, 1994,14(1): 27-33.
[37] Overholt B F, Lightdale C J, Wang K K, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international,partially blinded,randomized phase Ⅲ trial.[J].Gastrointest Endosc,2005,62(4):488-498.
[38]Pacifico R J,Wang K K,Wongkeesong L M,et al.Combined endoscopic mucosal resection and photodynamic therapy versus esophagectomy for management of early adenocarcinoma in Barrett's esophagus.[J].Clin Gastroenterol Hepatol,2003,1(4):252-257.
[39]Overholt B F,Panjehpour M,Haydek J M.Photodynamic therapy for Barrett's esophagus:follow-up in 100 patients.[J].Gastrointest Endosc,1999,49(1):1-7.
[40]Overholt B F,Panjehpour M,Halberg D L.Photodynamic therapy for Barrett's esophagus with dysplasia and/or early stage carcinoma:long-term results.[J].Gastrointest Endosc,2003,58(2):183-188.
[41]Gossner L,Stolte M,Sroka R,et al.Photodynamic ablation of high-grade dysplasia and early cancer in Barrett's esophagus by means of 5-aminolevulinic acid.[J].Gastroenterology,1998,114(3):448-455.
[42]Ortner M A,Zumbusch K,Liebetruth J,et al.Is topical delta- aminolevulinic acid adequate for photodynamic therapy in Barrett's esophagus? A pilot study.[J].Endoscopy,2002,34(8):611-616.
[43]McCaughan J S,Williams T E.Photodynamic therapy for endobronchial malignant disease:a prospective fourteen-year study.[J].J Thorac Cardiovasc Surg,1997,114(6):940-69467.
[44]Kato H.Photodynamic therapy for lung cancer—a review of 19 years'experience.[J].J Photochem Photobiol B,1998,42(2):96-99.
[45]Diaz-Jimenez J P,Martinez-Ballarin J E,Llunell A,et al.Efficacy and safety of photodynamic therapy versus Nd-YAG laser resection in NSCLC with airway obstruction.[J].Eur Respir J,1999,14(4):800-805.
[46]Moghissi K,Dixon K,Stringer M,et al.The place of bronchoscopic photodynamic therapy in advanced unresectable lung cancer: experience of 100 cases.[J]. Eur J Cardiothorac Surg, 1999, 15(1): 1-6.
[47] Furuse K, Fukuoka M, Kato H, et al. A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan Lung Cancer Photodynamic Therapy Study Group.[J]. J Clin Oncol, 1993, 11(10): 1852-1857.
[48] Imamura S, Kusunoki Y, Takifuji N, et al. Photodynamic therapy and/or external beam radiation therapy for roentgenologically occult lung cancer.[J]. Cancer, 1994, 73(6): 1608-1614.
[49] Ross P J, Grecula J, Bekaii-Saab T, et al. Incorporation of photodynamic therapy as an induction modality in non-small cell lung cancer.[J]. Lasers Surg Med, 2006, 38(10): 881-889.
[50] Baas P, van G I, Oppelaar H, et al. Enhancement of photodynamic therapy by mitomycin C: a preclinical and clinical study.[J]. Br J Cancer, 1996, 73(8): 945-951.
[51] Zoetmulder F A, van D J. Chest wall resection in the treatment of local recurrence of breast cancer.[J]. Eur J Surg Oncol, 1988, 14(2): 127—132.
[52] Hathaway C L, Rand R P, Moe R, et al. Salvage surgery for locally advanced and locally recurrent breast cancer.[J]. Arch Surg, 1994, 129(6): 582-587.
[53] Schuh M, Nseyo U O, Potter W R, et al. Photodynamic therapy for palliation of locally recurrent breast carcinoma.[J]. J Clin Oncol, 1987, 5(11): 1766-1770.
[54] Mang T S, Allison R, Hewson G, et al. A phase II/III clinical study of tin ethyl etiopurpurin (Purlytin)-induced photodynamic therapy for the treatment of recurrent cutaneous metastatic breast cancer.[J]. Cancer J Sci Am, 1998, 4(6): 378-384.
[55] Cairnduff F, Stringer M R, Hudson E J, et al. Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer.[J]. Br J Cancer, 1994, 69(3): 605-608.
[56] Baas P, van G I, Oppelaar H, et al. Enhancement of photodynamic therapy by mitomycin C: a preclinical and clinical study.[J]. Br J Cancer, 1996, 73(8): 945-951.
[57] Allison R R, Mang T S, Wilson B D. Photodynamic therapy for the treatment of nonmelanomatous cutaneous malignancies.[J]. Semin Cutan Med Surg, 1998, 17(2): 153-163.
[58] Gahlen J, Prosst R L, Stern J. [Photodynamic therapy in the gastrointestinal tract. Possibilities and limits][J]. Chirurg, 2002, 73(2): 122-131.
[59] Mimura S, Ito Y, Nagayo T, et al. Cooperative clinical trial of photodynamic therapy with photofrin II and excimer dye laser for early gastric cancer.[J]. Lasers Surg Med, 1996, 19(2): 168-172.
[60] Karanov S, Shopova M, Getov H. Photodynamic therapy in gastrointestinal cancer.[J]. Lasers Surg Med, 1991, 11(5): 395-398.
[61] Mimura S, Narahara H, Uehara H, et al. [Photodynamic therapy for gastric cancer][J]. Gan To Kagaku Ryoho, 1996,23(1): 41-46.
[62] Ell C, Gossner L, Hahn E G, et al. [Photodynamic therapy of a gastric stump carcinoma with curative intent. The first case report of a clinical application in Germany][J]. Dtsch Med Wochenschr, 1994,119(27): 951-955.
[63] Patrice T, Foultier M T, Yactayo S, et al. Endoscopic photodynamic therapy with haematoporphyrin derivative in gastroenterology.[J]. J Photochem Photobiol B, 1990,6(1-2): 157-165.
[64] Kelly J F, Snell M E, Berenbaum M C. Photodynamic destruction of human bladder carcinoma.[J]. Br J Cancer, 1975, 31(2): 237-244.
[65] Morales A. Treatment of superficial bladder cancer.[J]. Can Med Assoc J, 1980,122(10):1133-1138.
[66]Dougherty T J.Photodynamic therapy(PDT)of malignant tumors.[J].Crit Rev Oncol Hematol,1984,2(2):83-116.
[67]Rosenberg S J,Williams R D.Photodynamic therapy of bladder carcinoma.[J].Urol Clin North Am,1986,13(3):435-444.
[68]Benson R C.Laser photodynamic therapy for bladder cancer.[J].Mayo Clin Proc,1986,61(11):859-864.
[69]Nseyo U O,Dougherty T J,Boyle D G,et al.Whole bladder photodynamic therapy for transitional cell carcinoma of bladder.[J].Urology,1985,26(3):274-280.
[70]Berger A P,Steiner H,Stenzl A,et al.Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer:a single-center study.[J].Urology,2003,61(2):338-341.
[71]Nseyo U O,DeHaven J,Dougherty T J,et al.Photodynamic therapy(PDT)in the treatment of patients with resistant superficial bladder cancer:a long-term experience.[J].J Clin Laser Med Surg,1998,16(1):61-68.
[72]Kriegmair M,Baumgartner R,Lumper W,et al.Early clinical experience with 5-aminolevulinic acid for the photodynamic therapy of superficial bladder cancer.[J].Br J Urol,1996,77(5):667-671.
[73]Skyrme R J,French A J,Datta S N,et al.A phase-1 study of sequential mitomycin C and 5-aminolaevulinic acid-mediated photodynamic therapy in recurrent superficial bladder carcinoma.[J].BJU Int,2005,95(9):1206-1210.
[74]Pomer S,Grashev G,Sinn H,et al.Laser-induced fluorescence diagnosis and photodynamic therapy of human renal cell carcinoma.[J].Urol Int,1995,55(4):197-201.
[75]Popken G,Wetterauer U,Schultze-Seemann W.Kidney-preserving tumour resection in renal cell carcinoma with photodynamic detection by 5-aminolaevulinic acid:preclinical and preliminary clinical results.[J].BJU Int,1999,83(6):578-582.
[76]Ahn W S,Bae S M,Huh S W,et al.Necrosis-like death with plasma membrane damage against cervical cancer cells by photodynamic therapy.[J].Int J Gynecol Cancer,2004,14(3):475-482.
[77]Keefe K A,Chahine E B,DiSaia P J,et al.Fluorescence detection of cervical intraepithelial neoplasia for photodynamic therapy with the topical agents 5-aminolevulinic acid and benzoporphyrin-derivative monoacid ring.[J].Am J Obstet Gynecol,2001,184(6):1164-1169.
[78]Barnett A A,Haller J C,Cairnduff F,et al.A randomised,double-blind,placebo-controlled trial of photodynamic therapy using 5-aminolaevulinic acid for the treatment of cervical intraepithelial neoplasia.[J].Int J Cancer,2003,103(6):829-832.
[79]Copper M P,Tan I B,Oppelaar H,et al.Meta-tetra(hydroxyphenyl)chlorin photodynamic therapy in early-stage squamous cell carcinoma of the head and neck.[J].Arch Otolaryngol Head Neck Surg,2003,129(7):709-711.
[80]Hopper C,Kubler A,Lewis H,et al.mTHPC-mediated photodynamic therapy for early oral squamous cell carcinoma.[J].Int J Cancer,2004,111(1):138-146.
[81]Schuller D E,McCaughan J S,Rock R P.Photodynamic therapy in head and neck cancer.[J].Arch Otolaryngol,1985,111(6):351-355.
[82]Photoradiation therapy of head and neck cancer.[J].1984,170:681-691.
[83]Kubler A C,de C J,Hopper C,et al.Treatment of squamous cell carcinoma of the lip using Foscan-mediated photodynamic therapy.[J].Int J Oral Maxillofac Surg,2001,30(6):504-509.
[84]Keller G S,Doiron D R,Fisher G U.Photodynamic therapy in otolaryngology—head and neck surgery.[J].Arch Otolaryngol,1985,111(11):758-761.
[85]Lofgren L A,Hallgren S,Nilsson E,et al.Photodynamic therapy for recurrent nasopharyngeal cancer.[J].Arch Otolaryngol Head Neck Surg,1995,121(9):997-1002.
[86]Feyh J,Goetz A,Muller W,et al.Photodynamic therapy in head and neck surgery.[J].J Photochem Photobiol B,1990,7(2-4):353-358.
[87]Gluckman E,Roudet C,Hirsch I,et al.Prophylaxis of bacterial infections after bone marrow transplantation.A randomized prospective study comparing oral broad-spectrum nonabsorbable antibiotics(vancomycintobramycin-colistin)to absorbable antibiotics(ofloxacin-amoxicillin).[J].Chemotherapy,1991,37 Suppl 1:33-38.
[88]Kubler A C,de C J,Hopper C,et al.Treatment of squamous cell carcinoma of the lip using Foscan-mediated photodynamic therapy.[J].Int J Oral Maxillofac Surg,2001,30(6):504-509.
[89]Snyder J W,Greco W R,Bellnier D A,et al.Photodynamic therapy:a means to enhanced drug delivery to tumors.[J].Cancer Res,2003,63(23):8126-8131.
[90]Kirveliene V,Grazeliene G,Dabkeviciene D,et al.Schedule-dependent interaction between Doxorubicin and mTHPC-mediated photodynamic therapy in murine hepatoma in vitro and in vivo.[J].Cancer Chemother Pharmacol,2006,57(1):65-72.
[91]Chen B,Ahmed B,Landuyt W,et al.Potentiation of photodynamic therapy with hypericin by mitomycin C in the radiation-induced fibrosarcoma-1mouse tumor model.[J].Photochem Photobiol,2003,78(3):278-282.
[92]Gollnick S O,Vaughan L,Henderson B W.Generation of effective antitumor vaccines using photodynamic therapy.[J]. Cancer Res, 2002, 62(6): 1604-1608.
[93] Jalili A, Makowski M, Switaj T, et al. Effective photoimmunotherapy of murine colon carcinoma induced by the combination of photodynamic therapy and dendritic cells.[J]. Clin Cancer Res, 2004, 10(13): 4498-4508.
[94] Korbelik M, Sun J. Photodynamic therapy-generated vaccine for cancer therapy.[J]. Cancer Immunol Immunother, 2006, 55(8): 900-909.
[95] Dimitroff C J, Klohs W, Sharma A, et al. Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: implications for combination treatment with photodynamic therapy.[J]. Invest New Drugs, 1999,17(2): 121-135.
[96] Zhou Q, Olivo M, Lye K Y, et al. Enhancing the therapeutic responsiveness of photodynamic therapy with the antiangiogenic agents SU5416 and SU6668 in murine nasopharyngeal carcinoma models.[J]. Cancer Chemother Pharmacol, 2005, 56(6): 569-577.
[97] Ferrario A, Fisher A M, Rucker N, et al. Celecoxib and NS-398 enhance photodynamic therapy by increasing in vitro apoptosis and decreasing in vivo inflammatory and angiogenic factors.[J]. Cancer Res, 2005, 65(20): 9473-9478.
[98] Ferrario A, Gomer C J. Avastin enhances photodynamic therapy treatment of Kaposi's sarcoma in a mouse tumor model.[J]. J Environ Pathol Toxicol Oncol, 2006, 25(1-2): 251-259.
[99] El-Mofy A.M. Vitiligo and Psoralens. - Oxford: Pergamon Press, 1968. -147
[100] Wyss P. History of Photomedicine // Wyss P., Tadir Y., Tromberg B.J., Haller U. (eds): Photomedicine in Gynecology and Reproduction. - Basel: Karger, 2000. 4-11.
[101]Fahmy I.R.,Abu-Shady H.:Ammi majus linn:The isolation and properties of ammoidin,ammidin and majudin,and their effect in the treatment of leukoderma.[J]J.Pharm.Pharmacol.- 1948.21:499-503.
[102]Abels C.,Goetz A.E.A clinical protocol for photodynamic therapy//H.Honigsmann,G.Jori,A.R.Young(eds):The Fundamental Bases of Phototherapy.OEMF spa- Milano,1996.265-284.
[103]Rasmussen D.S.Ward G.E.Figge F.H.J.Fluorescence of human lymphatic and cancer tissues following high doses of intravenous hematoporphyrin [J]Cancer.1955.1:78-81.
[104]Tappeiner H.JesionekH.Therapeutische Versuche mit fluoreszierenden Stoffen[J]Munch.Med.Wschr.1903.50:2042-2044.
[105]Jesionek H.,Yappeiner H.Zur Behandlung der Hautcarcinome mit fluoreszierenden Stoffen[J]Dtsch.Arch.Klin.Med.1905.82:223-226.
[106]Tappeiner H.,Jodlbauer A.Uber die Wirkung der photodynamischen (fluoreszierenden)Stoffen auf Protozoen und Enzyme.[J].Dtsch.Arch.Klin.Med,1904,80:427-437.
[107]Hausmann W.H.Die sensibilisierende Wirkung des Hamatoporphyrins.[J].Biochem Z.1910.30:276-316.
[108]Hausmann W.H.Die sensibilisierende Wirkung tierischer Farbstoffe und ihre physiologische Bedeutung.[J].Wien.Klin.Wochenschr.1908.21:1527-1529.
[109]Meyer-Betz F.Untersuchung uber die biologische(photodynamische)Wirkung des Hamatoporphyrins und anderer Derivate des Blut- und Gallenfarbstoffs.[J].Dtsch.Arch.Klin.Med.- 1913.112:476-503.
[110]Policard A.Etudes sur les aspects offerts par des tumeurs experimentales examines a la lumiere de Wood.[J].CR Soc.Biol.1924.91:1423-1424.
[111]Lipson R.L.,Gray M.J.,Baldes E.J.Hematoporphyrin derivative for detection and management of cancer/Proc.9-th International Cancer Congress.- Tokyo,Japan,1966.- 393 p.
[112]Figge F.H.J.,Weiland G.S.,Manganiello O.J.Cancer detection and therapy.Affinity of neoplastic,embryonic,and traumatized tissues for porphyrins and metalloporphyrins.[J]Proc.Soc.Exp.Biol.Med.1948.68:640-641.
[113]Schwartz S.,Absolon K.,Vermund H.Some relationships of porphyrins,X-rays and tumors.[J].Bull.Minn.Univ.School Med.1955.27:7-13.
[114]丁新民.顾瑛.刘凡光等.光动力学治疗肿瘤患者3878例情况分析及近12年临床文献复习。[J].中国临床康复.2004,8(11):2014-2015.
[115]赵开弘.蒋丽金.竹红菌甲素在碱性和中性溶液中的结构变化.[J].有机化学,1989,9(3):252-254
[116]许娜飞.李景福.曹恩华等.Hela细胞对竹红菌甲素摄取的直接观察与动态过程分析.[J].生物物理学报.1995.11(2):261-266
[117]许娜飞.曹恩华.李景福.竹红菌甲素(HA)光敏致突变作用的研究。[J].生物物理学报,1995,11(4):604-608
[118]曹恩华.许娜飞.张健等.膜脂质过氧化物在光敏诱发细胞突变中的作用.[J1].激光生物学报.1998,7(1):3-7
[119]秦云才.韩东升.张伟等.光动力学疗效加放疗综合治疗食管癌的近期疗效分析[J].实用肿瘤学杂志,1997,11(12):109-111
[120]张景伟.王建华.刘法文等.食管癌放射治疗加光动力疗法长期生存分析[J].中国医师杂志,2003,5(8):1058-1060.
[121]雷银雪.食管不典型增生和早期癌的光动力学治疗[J].德国医学,1998,2(15):90
[122]陈广幸.李章生.汪森明等.光动力治疗中晚期中央型肺癌的临床初探.肿瘤防治杂志,2005,12(23):1798-1799.
[123]曾超英.杨栋.陈骥等.B超引导经皮介入光动力治疗中晚期肝癌30 例.[J].中国激光医学杂志,1996,5:63-66.
[124]曾超英.杨栋.黄萍等.光动力治疗肝癌远期疗效及影响因素探讨[J].中国激光医学杂志,2000,9:146-150.
[125]曾超英.黄萍.杨栋等.光动力作用对活体肝组织损伤研究[J].中国激光医学杂志,2000,9:141-145.
[126]陈静.王彩霞.宛苏等.CT引导下光动力学疗法治疗原发性肝癌的研究.[J].中华实验外科杂志,1994,11(6):341-2.
[127]汪连兴.陈拯民.瞿法康等.光动力学治疗中晚期大肠癌(附35例报告).[J].激光医学,1992,2(5):22-5.[
128]孙振权.罗国仪.光动力学治疗鼻咽癌57例分析.[J].中华肿瘤杂志,1990,12(2):120-121
[129]孙振权.罗国仪.激光光动力学治疗复发性鼻咽癌的研究 附191例分析.[J].中国激光医学杂志,1996,5(3):134
[130]卢明.黄鸿年.绦博.血卟啉分离物(HPS)放射增敏效应的实验研究.[J].中国肿瘤临床,1987,14:341
[131]胡德恩.林祥松.王晓风放射治疗鼻咽癌患者免疫状态的影响.[J].肿瘤防治研究,1987,14:21
[132]粱亚云.王耐勤.于刚.光敏剂一血卟啉衍生物(HPD)对小鼠免疫功能的影响.[J].上海免疫学杂志.1985,45-79
[133]陆明芳.光动力学疗法试治放疗后复发性鼻咽癌.[J].中国激光医学杂志.2000,9(3):164-165
[134]漆其光.廖卫国.温清泉等.激光动力学治疗早期喉癌的临床分析.[J].广东医学,2005,26(7):962-963.
[135]江新.激光和光动力学治疗复发性鼻窦癌.[J].应用激光.1992,12(5):237-238.
[136]阮珊真.盛月霞.光敏疗法治疗颈淋巴结转移癌2例报道.[J].肿瘤.1989,9:216-216.