尖锐湿疣患者宫颈高危型人乳头瘤病毒感染情况的调查及人乳头瘤病毒临床和亚临床感染治疗的研究
|
摘要
尖锐湿疣患者宫颈高危型人乳头瘤病毒感染情况的调查及人乳头瘤病毒临床和亚临床感染治疗的研究
背景和目的：人类乳头瘤病毒(human papillomavirus, HPV)是一种环状双链脱氧核糖核酸(deoxyribonucleic acid, DNA)病毒。目前发现的100多种HPV型别中,约40多种可特异性的感染肛门生殖器部位的皮肤和粘膜。按照HPV所导致皮损的性质,人们把HPV型别分为高危型(high risk, HR)和低危型(low risk, LR)。大量研究表明,宫颈HR-HPV感染是宫颈上皮内瘤变(cervical intraepithelial neoplasia, CIN)和宫颈癌发病的必要条件。LR-HPV6、11在尖锐湿疣组织中是最常见的型别。流行病学调查发现,部分免疫功能正常的尖锐湿疣(condylomata acuminata, CA)患者疣组织中同时合并LR-HPV和HR-HPV(?)感染,最常见合并感染的HR型别是HPV16。丹麦和瑞典科学家分别进行的队列研究都提示：CA患者有较高的发生宫颈痛或宫颈原位癌的危险。但是并没有直接的数据说明CA患者宫颈HR-HPV感染几率是否大于普通女性。女性宫颈持续感染高危型HPV不但为宫颈癌的发生埋下隐患,而且增加了病毒在性伴侣之间相互传播的机会。对于宫颈HR-HPV的亚临床感染,尽管人们已经意识到其危害性,但是目前并没有一种被证实有效的方法来消除宫颈HPV感染。相对于传统的治疗方法,5—氨基酮戊酸结合光动力治疗(photodynamic therapy using aminolevulinic acid, ALA-PDT)对于数目较少或体积较小的CA有较高的治愈率和较低的复发率。其作用机制除了对CA组织增生活跃细胞的光毒性作用以外,有研究发现ALA-PDT本身有抗病毒的作用,但是目前没有关于ALA-PDT抗HPV及相关机制的研究。由于受到皮肤角质层和细胞膜的阻挡,ALA在皮肤组织中的渗透有限,这是ALA-PDT对体积较大或数目较多CA疗效不佳的原因。不同程度的冷冻治疗可以造成组织结构和细胞膜的破坏甚至坏死。理论上,皮肤角质层和角质形成细胞膜连续性的破坏可以增加ALA的渗透,继而能提高ALA-PDT的疗效。综上所述,本实验目的是：1、调查女性尖锐湿疣患者宫颈HR-HPV的感染状况,从而明确是否有对这部分患者进行宫颈HR-HPV检测和随访的必要性；2、研究ALA-PDT对Hela细胞内HPV18E6、E7基因表达的影响,从而探索除了细胞死亡途径,ALA-PDT是否还存在其他抗HPV感染的机制；3、研究冷冻联合ALA-PDT作用于Hela细胞的效应,以比较联合治疗的疗效是否优于单独治疗；4、研究ALA-PDT治疗宫颈HR-HPV亚临床感染的临床疗效；5、研究
冷冻联合ALA-PDT治疗肛门外生殖器部位体积较大或数量较多尖锐湿疣的临床疗效。
方法：
1尖锐湿疣女性患者宫颈高危型人乳头瘤病毒感染情况的调查：
1.1用第二代基因杂交捕获(hybrid capture-Ⅱ, HC-Ⅱ)人乳头瘤病毒的方法检测142例外阴尖锐湿疣女性患者及212例健康女性宫颈脱落细胞HR-HPVDNA;
1.2将两组宫颈HR-HPV感染的阳性率及病毒载量进行统计学比较,得到外阴尖锐湿疣患者宫颈HR-HPV感染率和病毒载量与普通人群比较的统计学差异。
25—氨基酮戊酸结合光动力治疗单独或联合冷冻治疗对Hela细胞凋亡及HPV18病毒相关基因表达的影响：
2.1将Hela细胞分为治疗1组(20%ALA-PDT),治疗2组(1%ALA-PDT),治疗3组(0.1%ALA-PDT),治疗4组(0.002%ALA-PDT),治疗5组(冷冻加0.002%ALA-PDT),对照组(冷冻组),空白组(无冷冻无ALA-PDT)。
2.2分别给予各组相应的方法处置,12h后,用流式细胞仪(flow cytometry, FCM)检测各组细胞的凋亡情况,用逆转录聚合酶链反应(reverse transcription polymerase chain reaction, RT-PCR)检测各组细胞中人乳头癌病毒18E6、E7mRNA的表达情况,quantity one4.6.2凝胶定量软件进行灰度分析。
35—氨基酮戊酸结合光动力治疗宫颈高危型人乳头瘤病毒业临床感染的临床疗效研究：
3.1将35例宫颈HR-HPV阳性患者随机分为ALA-PDT治疗组和无治疗的对照组；
3.2治疗组治疗1次后、对照组从第一次检测到高危型人乳头瘤病毒阳性后,三个月复查宫颈人乳头瘤病毒感染情况。
3.3比较两组检测结果和副反应。用统计产品与服务解决方案17.0软件(statistical product and service solutions, SPSS17.0)对实验结果进行统计学分析。
4冷冻联合5—氨基酮戊酸光动力治疗与冷冻单独治疗多发性尖锐湿疣临床疗效的随机对照研究
4.180例多发性尖锐湿疣的患者随机分为两组,分别接受冷冻加5—氨基酮戊酸光动力治疗(n=40)和冷冻加安慰剂光动力治疗(n=40)。冷冻疣体之后在患处及周围5mm范围外敷5—氨基酮戊酸或安慰剂溶液,3h之后用红光(波长635nm,100mW/cm2,100J/cm2)照射15min。如皮损未消退7天后重复治疗。
4.2比较两组的完全反应率、复发率和副作用。
结果：
1. HR-HPV阳性率,尖锐湿疣组为54.2%(77/142),健康对照组为13.2%(28/212),两组阳性率有显最著差异(P<0.05)。病毒载量(relative light units/positive control, RLU/PC),尖锐湿疣组1～<1024例,10-<10016例,100～<100022例,≥100015例。健康对照组1-<1010例,10-<10010例,100-<10007例,≥10001例,尖锐湿疣组病毒载量≥1000者与对照组比较有显著差异(P<0.05)。
2.各组Hela细胞流式细胞仪检测结果：治疗1组10.84%存活,0.23%凋亡,86.01%死亡；治疗2组8.59%存活,14.83%凋亡,74.54%死亡；治疗3组81.17%存活,2.80%凋亡,8.55%死亡；治疗4组83.98%存活,1.66%凋亡,11.16%死亡；治疗5组18.06%存活,10.80%凋亡,67.99%死亡；对照组23.05%存活,9.40%凋亡,58.85%死亡；空白组88.78%存活,1.00%凋亡,7.63%死亡。各组Hela细胞人乳头瘤病毒18E6、E7mRNA表达情况：治疗1组、2组、3组、4组、5组、对照组E7mRNA分别为空白组的26.81%、41.20%、61.83%、71.75%、70.30%、93.26%；治疗1组、2组E6mRNA没有表达,3组、4组、5组、对招租E6mRNA分别为空白组的34.02%、49.76%、41.67%、97.67%。
3.治疗组共17人,其中10人高危型人乳头瘤病毒转阴,7人阳性。对照组18人中1人高危型人乳头瘤病毒转阴,17人阳性。治疗组与对照组间转阴率有显著差异(P<0.05)。治疗组中的副反应包括轻度到中度的疼痛、水肿、糜烂,没有发生治疗部位的感染、溃疡、瘢痕及畸形。
4.2次治疗后,联合治疗组(冷冻加5—氨基酮戊酸光动力治疗)和冷冻组在肛周,尿道口和外生殖器尖锐湿疣的完全反应率分别为32.4%(36/111)和32.6%(43/132)(P>0.05),100%(32/32)和54.5%(18/33)(P<0.05),94.2%(129/137)和50.5%(56/111)(P<0.05)；复发率分别为24.3%(27/111)和31.1%(41/132)(P>0.05),9.4%(3/32)和39.4%(13/33)(P<0.05),3.6%(5/137)和31.5%(35/111)(P<0.05)。两组的副反应包括轻度到中度疼痛、水肿、糜烂和色素沉着,无感染、溃疡、瘢痕或尿道口畸形。
结论：
1.外阴尖锐湿疣患者宫颈HR-HPV阳性率和高病毒载量者较普通人群显著增高,应重视这部分患者宫颈HR-HPV的检测和随访。
2.5—氨基=酮戊酸结合光动力治疗可以抑制Hela细胞内人乳头瘤病毒18E6、E7mRNA的表达；冷冻可增强5—氨基酮戊酸结合光动力治疗对Hela细胞的杀伤效应和对细胞内人乳头瘤病毒18E6、E7mRNA表达的抑制作用。
3.5—氨基酮戊酸结合光动力治疗是一种安全、有效的治疗宫颈人乳头瘤病毒感染的方法。
4.相对于冷冻单独治疗,冷冻联合5—氨基酮戊酸光动力治疗肛门外生殖器多发性尖锐湿疣是一种更加有效的治疗方案。
Background and objectives:Human papillomavirus (HPV) are double stranded DNA viruses, which are divided into High risk (LR) and Low risk (LR) genotypes according to a spectrum of anogenital region epithelial proliferative diseases ranging from benign wart to intraepithelial neoplasms associating with HPV. It is now recognized that HR-HPV infection is a necessary cause for cervical intraepithelial neoplasia (CIN) and cervical cancer. LR-HPV6,11are most often detected genotypes in condylomata acuminata (CA) lesions. Epidemiology studies demonstrated that a high percentage of CA lesions contain LR and HR types and HPV16is the most frequently detected HR-HPV type in patients with normal immunity. Two large cohort studies of patients with CA revealed that condylomata acuminata are strongly associated with increased risk of cervical cancer in situ. So we speculate that the infection rate of cervical HR-HPV of females with CA is significantly higher than normal females. Cervical persistent infection of HR-HPV not only might result cervical cancer, but increase transmission chances of virus between sexual partners. Although associations between cervical subclinical infection and cervical cancer have been revealed, there is no effective method to clear HPV in cervix. Topical photodynamic therapy using aminolevulinic acid (ALA-PDT) is a technique for superficial CA with higher recovery rates and lower recurrence rates than the conventional treatments. The main mechanism contributing to the efficacy of ALA-PDT is the phototoxicity to the proliferative cells. In addition, ALA-PDT has been shown to have some antiviral properties. However, there is no research about the anti-HPV property of ALA-PDT by far. The topical application of ALA results in a shallow penetration depth into tissue, which prevents ALA-PDT from sufficiently entering into and destroying multiple or bulky warts lesions. The tissue response varies with the intensity of the cryotherapy ranges from inflammatory response to tissue destruction. Theoretically, the loss or the alteration in the integrity of the tissue structure and the damage of cell constituents resulting from cryotherapy might facilitate ALA penetration int the cells of the wart lesion, which could improve the efficacy of ALA-PDT. The objectives of the study include investigate cervical HR-HPV infection situation in female patients with condylomata acuminate, studying the influence of5-aminolaevulinic acid and photodynamic therapy vs. cryotherapy plus5-aminolaevulinic acid and photodynamic therapy to Hela cells and HPV18E6、E7gene expression, studying the clinical efficacy of5-aminolaevulinic acid and photodynamic therapy for cervical HR-HPV infection and studying cryotherapy plus photodynamic therapy vs. cryotherapy in the treatment of multiple condylomata acuminata.
Method:
1Study of cervical high risk human papillomavirus infection rate in patients with condylomata acuminata.
1.1Cervical exfoliated cells of142patients with CA and212healthy females were detected by hybrid capture II.
1.2The positive rates and virus loads of HR-HPV of two groups were compared.
2The influence of5-aminolaevulinic acid and photodynamic therapy vs. cryotherapy plus5-aminolaevulinic acid and photodynamic therapy to Hela cells and HPV18E6、 E7gene expression.
2.1Hela cells were divided into treatment group1(20%ALA-PDT), group2(1%ALA-PDT), group3(0.1%ALA-PDT), group4(0.002%ALA-PDT), group5(cryotherapy plus0.002%ALA-PDT), control group (cryotherapy alone) and blank group (no cryotherapy or ALA-PDT)
2.2After12hours of treatment, each group was detected by flow cytometry (FCM). HPV18E6, E7were detected by reverse transcription polymerase chain reaction (RT-PCR) and quantity one software.
3Study of the clinical efficacy of5-aminolaevulinic acid and photodynamic therapy treatment for cervical HR-HPV infection.
3.1Thirty five patients with cervical HR-HPV infection were divided into ALA-PDT group (n=17) and control group (n=18). A20%ALA solution was applied to the cervix area3h before illumination with red light (635nm,100mW/cm2,100J/cm2).
3.2After3month of treatment, cervical HR-HPV of patients in ALA-PDT group and control group were detected.
3.3The negative rates and adverse effects in the two groups were analyzed.
4A randomized clinical comparative study of cryotherapy plus photodynamic therapy vs. cryotherapy in the treatment of multiple condylomata acuminata.
4.1Eighty patients with multiple CA receive cryotherapy plus ALA-PDT (n=40) or cryotherapy plus placebo-PDT (n=40). After cryotherapy, a20%ALA or a placebo solution was applied to the CA area3h before illumination with red light (635nm,100mW/cm2,100J/cm2). The treatment was repeated7days after the first treatment if the lesions were not completely resolved.
4.2The complete response rate, recurrence rate and adverse effects in the two groups were analyzed.
Results:
1. The positive rates of CA group and control group were54.2%and13.2%, respectively, which was significantly different between two groups (P<0.05). The virus loads (RLU/PC) were divided into four grades. Patients with1～<10grade were24and10,10～<100grade were16and10,100～<1000grade were22and7,>1000grade were15and1in CA group and control group, respectively. The number of patients with high grade virus loads (≥1000) in CA group was significantly higher than that in control group (P<0.05).
2. the normal rates, apoptosis rates and dead rates of cells of the seven groups were10.84%,0.23%,86.01%in group1;8.59%,14.83%,74.54%in group2;81.17%,2.80%.8.55%in group3;83.98%,1.66%,11.16%in group4;18.06%,10.80%,67.99%in group5;23.05%,9.40%,58.85%in the control group and88.78%,1.00%,7.63%in the blank group, respectively. The expression rates of E6in group1-5and control group compared with the blank group were0,0,34.02%,49.76%,41.67%, and97.67%, respectively. The expression rates of E7in group1-5and control group compared with the blank group were26.81%,41.20%,61.83%,71.75%,70.30%and93.26%, respectively.
3. After one treatments, the negative rates of the ALA-PDT and control group were58.82%(10/17),5.6%(1/18)(p<0.05). The adverse effects in the ALA-PDT group included mild to moderate pain, edema and erosion, without any infection, ulcers, scarring or cervical malformations.
4. After two treatments, the complete response rates in the combined group and cryotherapy group were32.4%(36/111) and32.6%(43/132) in the anal area (P>0.05),100%(32/32) and54.5%(18/33) in the urethral meatus (P<0.05), and94.2%(129/137) and50.5%(56/111) in the external genitals (P<0.05), respectively. The recurrence rates in the combined group and cryotherapy group were24.3%(27/111) and31.1%(41/132) in the anal area (P>0.05),9.4%(3/32) and39.4%(13/33) in the urethral meatus (P<0.05), and3.6%(5/137) and31.5%(35/111) in the external genitals (P<0.05), respectively. The adverse effects in each group included mild to moderate pain, edema, erosion and hypopigmentation, without any infection, ulcers, scarring or urethral malformations.
Conclusions:
1. Detection of cervical HR-HPV in patients with CA should be highly valued because HR-HPV infection rate and virus loads of CA patients were significantly higher than those of healthy females.
2. ALA-PDT can inhibit the expression of HPV18E6, E7mRNA in Hela cells; cryotherapy plus ALA-PDT is a more effective regimen for killing Hela cells and inhibiting the expression of HPV18E6、E7mRNA compared with ALA-PDT alone.
3. ALA-PDT is a safe and effective therapeutic method for cervical HR-HPV infection.
4. Cryotherapy plus ALA-PDT is a more effective regimen for the treatment of multiple CA compared with cryotherapy alone.
背景和目的：人类乳头瘤病毒(human papillomavirus, HPV)是一种环状双链脱氧核糖核酸(deoxyribonucleic acid, DNA)病毒。目前发现的100多种HPV型别中,约40多种可特异性的感染肛门生殖器部位的皮肤和粘膜。按照HPV所导致皮损的性质,人们把HPV型别分为高危型(high risk, HR)和低危型(low risk, LR)。大量研究表明,宫颈HR-HPV感染是宫颈上皮内瘤变(cervical intraepithelial neoplasia, CIN)和宫颈癌发病的必要条件。LR-HPV6、11在尖锐湿疣组织中是最常见的型别。流行病学调查发现,部分免疫功能正常的尖锐湿疣(condylomata acuminata, CA)患者疣组织中同时合并LR-HPV和HR-HPV(?)感染,最常见合并感染的HR型别是HPV16。丹麦和瑞典科学家分别进行的队列研究都提示：CA患者有较高的发生宫颈痛或宫颈原位癌的危险。但是并没有直接的数据说明CA患者宫颈HR-HPV感染几率是否大于普通女性。女性宫颈持续感染高危型HPV不但为宫颈癌的发生埋下隐患,而且增加了病毒在性伴侣之间相互传播的机会。对于宫颈HR-HPV的亚临床感染,尽管人们已经意识到其危害性,但是目前并没有一种被证实有效的方法来消除宫颈HPV感染。相对于传统的治疗方法,5—氨基酮戊酸结合光动力治疗(photodynamic therapy using aminolevulinic acid, ALA-PDT)对于数目较少或体积较小的CA有较高的治愈率和较低的复发率。其作用机制除了对CA组织增生活跃细胞的光毒性作用以外,有研究发现ALA-PDT本身有抗病毒的作用,但是目前没有关于ALA-PDT抗HPV及相关机制的研究。由于受到皮肤角质层和细胞膜的阻挡,ALA在皮肤组织中的渗透有限,这是ALA-PDT对体积较大或数目较多CA疗效不佳的原因。不同程度的冷冻治疗可以造成组织结构和细胞膜的破坏甚至坏死。理论上,皮肤角质层和角质形成细胞膜连续性的破坏可以增加ALA的渗透,继而能提高ALA-PDT的疗效。综上所述,本实验目的是：1、调查女性尖锐湿疣患者宫颈HR-HPV的感染状况,从而明确是否有对这部分患者进行宫颈HR-HPV检测和随访的必要性；2、研究ALA-PDT对Hela细胞内HPV18E6、E7基因表达的影响,从而探索除了细胞死亡途径,ALA-PDT是否还存在其他抗HPV感染的机制；3、研究冷冻联合ALA-PDT作用于Hela细胞的效应,以比较联合治疗的疗效是否优于单独治疗；4、研究ALA-PDT治疗宫颈HR-HPV亚临床感染的临床疗效；5、研究
冷冻联合ALA-PDT治疗肛门外生殖器部位体积较大或数量较多尖锐湿疣的临床疗效。
方法：
1尖锐湿疣女性患者宫颈高危型人乳头瘤病毒感染情况的调查：
1.1用第二代基因杂交捕获(hybrid capture-Ⅱ, HC-Ⅱ)人乳头瘤病毒的方法检测142例外阴尖锐湿疣女性患者及212例健康女性宫颈脱落细胞HR-HPVDNA;
1.2将两组宫颈HR-HPV感染的阳性率及病毒载量进行统计学比较,得到外阴尖锐湿疣患者宫颈HR-HPV感染率和病毒载量与普通人群比较的统计学差异。
25—氨基酮戊酸结合光动力治疗单独或联合冷冻治疗对Hela细胞凋亡及HPV18病毒相关基因表达的影响：
2.1将Hela细胞分为治疗1组(20%ALA-PDT),治疗2组(1%ALA-PDT),治疗3组(0.1%ALA-PDT),治疗4组(0.002%ALA-PDT),治疗5组(冷冻加0.002%ALA-PDT),对照组(冷冻组),空白组(无冷冻无ALA-PDT)。
2.2分别给予各组相应的方法处置,12h后,用流式细胞仪(flow cytometry, FCM)检测各组细胞的凋亡情况,用逆转录聚合酶链反应(reverse transcription polymerase chain reaction, RT-PCR)检测各组细胞中人乳头癌病毒18E6、E7mRNA的表达情况,quantity one4.6.2凝胶定量软件进行灰度分析。
35—氨基酮戊酸结合光动力治疗宫颈高危型人乳头瘤病毒业临床感染的临床疗效研究：
3.1将35例宫颈HR-HPV阳性患者随机分为ALA-PDT治疗组和无治疗的对照组；
3.2治疗组治疗1次后、对照组从第一次检测到高危型人乳头瘤病毒阳性后,三个月复查宫颈人乳头瘤病毒感染情况。
3.3比较两组检测结果和副反应。用统计产品与服务解决方案17.0软件(statistical product and service solutions, SPSS17.0)对实验结果进行统计学分析。
4冷冻联合5—氨基酮戊酸光动力治疗与冷冻单独治疗多发性尖锐湿疣临床疗效的随机对照研究
4.180例多发性尖锐湿疣的患者随机分为两组,分别接受冷冻加5—氨基酮戊酸光动力治疗(n=40)和冷冻加安慰剂光动力治疗(n=40)。冷冻疣体之后在患处及周围5mm范围外敷5—氨基酮戊酸或安慰剂溶液,3h之后用红光(波长635nm,100mW/cm2,100J/cm2)照射15min。如皮损未消退7天后重复治疗。
4.2比较两组的完全反应率、复发率和副作用。
结果：
1. HR-HPV阳性率,尖锐湿疣组为54.2%(77/142),健康对照组为13.2%(28/212),两组阳性率有显最著差异(P<0.05)。病毒载量(relative light units/positive control, RLU/PC),尖锐湿疣组1～<1024例,10-<10016例,100～<100022例,≥100015例。健康对照组1-<1010例,10-<10010例,100-<10007例,≥10001例,尖锐湿疣组病毒载量≥1000者与对照组比较有显著差异(P<0.05)。
2.各组Hela细胞流式细胞仪检测结果：治疗1组10.84%存活,0.23%凋亡,86.01%死亡；治疗2组8.59%存活,14.83%凋亡,74.54%死亡；治疗3组81.17%存活,2.80%凋亡,8.55%死亡；治疗4组83.98%存活,1.66%凋亡,11.16%死亡；治疗5组18.06%存活,10.80%凋亡,67.99%死亡；对照组23.05%存活,9.40%凋亡,58.85%死亡；空白组88.78%存活,1.00%凋亡,7.63%死亡。各组Hela细胞人乳头瘤病毒18E6、E7mRNA表达情况：治疗1组、2组、3组、4组、5组、对照组E7mRNA分别为空白组的26.81%、41.20%、61.83%、71.75%、70.30%、93.26%；治疗1组、2组E6mRNA没有表达,3组、4组、5组、对招租E6mRNA分别为空白组的34.02%、49.76%、41.67%、97.67%。
3.治疗组共17人,其中10人高危型人乳头瘤病毒转阴,7人阳性。对照组18人中1人高危型人乳头瘤病毒转阴,17人阳性。治疗组与对照组间转阴率有显著差异(P<0.05)。治疗组中的副反应包括轻度到中度的疼痛、水肿、糜烂,没有发生治疗部位的感染、溃疡、瘢痕及畸形。
4.2次治疗后,联合治疗组(冷冻加5—氨基酮戊酸光动力治疗)和冷冻组在肛周,尿道口和外生殖器尖锐湿疣的完全反应率分别为32.4%(36/111)和32.6%(43/132)(P>0.05),100%(32/32)和54.5%(18/33)(P<0.05),94.2%(129/137)和50.5%(56/111)(P<0.05)；复发率分别为24.3%(27/111)和31.1%(41/132)(P>0.05),9.4%(3/32)和39.4%(13/33)(P<0.05),3.6%(5/137)和31.5%(35/111)(P<0.05)。两组的副反应包括轻度到中度疼痛、水肿、糜烂和色素沉着,无感染、溃疡、瘢痕或尿道口畸形。
结论：
1.外阴尖锐湿疣患者宫颈HR-HPV阳性率和高病毒载量者较普通人群显著增高,应重视这部分患者宫颈HR-HPV的检测和随访。
2.5—氨基=酮戊酸结合光动力治疗可以抑制Hela细胞内人乳头瘤病毒18E6、E7mRNA的表达；冷冻可增强5—氨基酮戊酸结合光动力治疗对Hela细胞的杀伤效应和对细胞内人乳头瘤病毒18E6、E7mRNA表达的抑制作用。
3.5—氨基酮戊酸结合光动力治疗是一种安全、有效的治疗宫颈人乳头瘤病毒感染的方法。
4.相对于冷冻单独治疗,冷冻联合5—氨基酮戊酸光动力治疗肛门外生殖器多发性尖锐湿疣是一种更加有效的治疗方案。
Background and objectives:Human papillomavirus (HPV) are double stranded DNA viruses, which are divided into High risk (LR) and Low risk (LR) genotypes according to a spectrum of anogenital region epithelial proliferative diseases ranging from benign wart to intraepithelial neoplasms associating with HPV. It is now recognized that HR-HPV infection is a necessary cause for cervical intraepithelial neoplasia (CIN) and cervical cancer. LR-HPV6,11are most often detected genotypes in condylomata acuminata (CA) lesions. Epidemiology studies demonstrated that a high percentage of CA lesions contain LR and HR types and HPV16is the most frequently detected HR-HPV type in patients with normal immunity. Two large cohort studies of patients with CA revealed that condylomata acuminata are strongly associated with increased risk of cervical cancer in situ. So we speculate that the infection rate of cervical HR-HPV of females with CA is significantly higher than normal females. Cervical persistent infection of HR-HPV not only might result cervical cancer, but increase transmission chances of virus between sexual partners. Although associations between cervical subclinical infection and cervical cancer have been revealed, there is no effective method to clear HPV in cervix. Topical photodynamic therapy using aminolevulinic acid (ALA-PDT) is a technique for superficial CA with higher recovery rates and lower recurrence rates than the conventional treatments. The main mechanism contributing to the efficacy of ALA-PDT is the phototoxicity to the proliferative cells. In addition, ALA-PDT has been shown to have some antiviral properties. However, there is no research about the anti-HPV property of ALA-PDT by far. The topical application of ALA results in a shallow penetration depth into tissue, which prevents ALA-PDT from sufficiently entering into and destroying multiple or bulky warts lesions. The tissue response varies with the intensity of the cryotherapy ranges from inflammatory response to tissue destruction. Theoretically, the loss or the alteration in the integrity of the tissue structure and the damage of cell constituents resulting from cryotherapy might facilitate ALA penetration int the cells of the wart lesion, which could improve the efficacy of ALA-PDT. The objectives of the study include investigate cervical HR-HPV infection situation in female patients with condylomata acuminate, studying the influence of5-aminolaevulinic acid and photodynamic therapy vs. cryotherapy plus5-aminolaevulinic acid and photodynamic therapy to Hela cells and HPV18E6、E7gene expression, studying the clinical efficacy of5-aminolaevulinic acid and photodynamic therapy for cervical HR-HPV infection and studying cryotherapy plus photodynamic therapy vs. cryotherapy in the treatment of multiple condylomata acuminata.
Method:
1Study of cervical high risk human papillomavirus infection rate in patients with condylomata acuminata.
1.1Cervical exfoliated cells of142patients with CA and212healthy females were detected by hybrid capture II.
1.2The positive rates and virus loads of HR-HPV of two groups were compared.
2The influence of5-aminolaevulinic acid and photodynamic therapy vs. cryotherapy plus5-aminolaevulinic acid and photodynamic therapy to Hela cells and HPV18E6、 E7gene expression.
2.1Hela cells were divided into treatment group1(20%ALA-PDT), group2(1%ALA-PDT), group3(0.1%ALA-PDT), group4(0.002%ALA-PDT), group5(cryotherapy plus0.002%ALA-PDT), control group (cryotherapy alone) and blank group (no cryotherapy or ALA-PDT)
2.2After12hours of treatment, each group was detected by flow cytometry (FCM). HPV18E6, E7were detected by reverse transcription polymerase chain reaction (RT-PCR) and quantity one software.
3Study of the clinical efficacy of5-aminolaevulinic acid and photodynamic therapy treatment for cervical HR-HPV infection.
3.1Thirty five patients with cervical HR-HPV infection were divided into ALA-PDT group (n=17) and control group (n=18). A20%ALA solution was applied to the cervix area3h before illumination with red light (635nm,100mW/cm2,100J/cm2).
3.2After3month of treatment, cervical HR-HPV of patients in ALA-PDT group and control group were detected.
3.3The negative rates and adverse effects in the two groups were analyzed.
4A randomized clinical comparative study of cryotherapy plus photodynamic therapy vs. cryotherapy in the treatment of multiple condylomata acuminata.
4.1Eighty patients with multiple CA receive cryotherapy plus ALA-PDT (n=40) or cryotherapy plus placebo-PDT (n=40). After cryotherapy, a20%ALA or a placebo solution was applied to the CA area3h before illumination with red light (635nm,100mW/cm2,100J/cm2). The treatment was repeated7days after the first treatment if the lesions were not completely resolved.
4.2The complete response rate, recurrence rate and adverse effects in the two groups were analyzed.
Results:
1. The positive rates of CA group and control group were54.2%and13.2%, respectively, which was significantly different between two groups (P<0.05). The virus loads (RLU/PC) were divided into four grades. Patients with1～<10grade were24and10,10～<100grade were16and10,100～<1000grade were22and7,>1000grade were15and1in CA group and control group, respectively. The number of patients with high grade virus loads (≥1000) in CA group was significantly higher than that in control group (P<0.05).
2. the normal rates, apoptosis rates and dead rates of cells of the seven groups were10.84%,0.23%,86.01%in group1;8.59%,14.83%,74.54%in group2;81.17%,2.80%.8.55%in group3;83.98%,1.66%,11.16%in group4;18.06%,10.80%,67.99%in group5;23.05%,9.40%,58.85%in the control group and88.78%,1.00%,7.63%in the blank group, respectively. The expression rates of E6in group1-5and control group compared with the blank group were0,0,34.02%,49.76%,41.67%, and97.67%, respectively. The expression rates of E7in group1-5and control group compared with the blank group were26.81%,41.20%,61.83%,71.75%,70.30%and93.26%, respectively.
3. After one treatments, the negative rates of the ALA-PDT and control group were58.82%(10/17),5.6%(1/18)(p<0.05). The adverse effects in the ALA-PDT group included mild to moderate pain, edema and erosion, without any infection, ulcers, scarring or cervical malformations.
4. After two treatments, the complete response rates in the combined group and cryotherapy group were32.4%(36/111) and32.6%(43/132) in the anal area (P>0.05),100%(32/32) and54.5%(18/33) in the urethral meatus (P<0.05), and94.2%(129/137) and50.5%(56/111) in the external genitals (P<0.05), respectively. The recurrence rates in the combined group and cryotherapy group were24.3%(27/111) and31.1%(41/132) in the anal area (P>0.05),9.4%(3/32) and39.4%(13/33) in the urethral meatus (P<0.05), and3.6%(5/137) and31.5%(35/111) in the external genitals (P<0.05), respectively. The adverse effects in each group included mild to moderate pain, edema, erosion and hypopigmentation, without any infection, ulcers, scarring or urethral malformations.
Conclusions:
1. Detection of cervical HR-HPV in patients with CA should be highly valued because HR-HPV infection rate and virus loads of CA patients were significantly higher than those of healthy females.
2. ALA-PDT can inhibit the expression of HPV18E6, E7mRNA in Hela cells; cryotherapy plus ALA-PDT is a more effective regimen for killing Hela cells and inhibiting the expression of HPV18E6、E7mRNA compared with ALA-PDT alone.
3. ALA-PDT is a safe and effective therapeutic method for cervical HR-HPV infection.
4. Cryotherapy plus ALA-PDT is a more effective regimen for the treatment of multiple CA compared with cryotherapy alone.
引文
1 Greer CE, Wheeler CM, Ladner MB, et al. Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts [J]. J Clin Microbiol,1995,33:2058-63.
2 Brown DR, Schroeder JM, Bryan JT, et al. Detection of multiple human papillomavirus types in condylomata acuminata lesions from otherwise healthy and immunosuppressed patients [J]. J Clin Microbiol,1999,37:3316-22.
3 Friis S, Kjaer SK, Frisch M, et al. Cervical intraepithelial neoplasia, anogenital cancer, and other cancer types in women after hospitalization for condylomata acuminata [J]. J Infect Dis,1997,175:743-8.
4 Nordenvall C, Chang ET, Adami HO, et al. Cancer risk among patients with condylomata acuminata [J]. Int J Cancer,2006,119:888-93.
5 Ayala F, Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24:237-243.
6 Rossi R, Bruscino N, Ricceri F, Grazzini M, Dindelli M, Lotti T. Photodynamic treatment for viral infections of the skin [J]. G Ital Dermatol Venereol.2009,144:79-83.
7 Prignano F, Lotti T, Spallanzani A, Berti S, de Giorgi V, Moretti S. Sequential effects of photodynamic treatment of basal cell carcinoma [J]. J Cutan Pathol,2009,36:409-416.
1 Ross EV, Romero R, Kollias N, et al. Selectivity of protoporphyrin IX fluorescence for condylomata after topical application of 5-aminolevulinic acid:implications for photodynamic treatment [J]. Br J Dermatol,1997,137:736-42.
2 Ayala F. Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24(5):237-43.
3 Bulkmans, N. W., J. Berkhof, L. Rozendaal, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neo-plasia grade 3 and cancer:5-year follow-up of a randomised controlled implementation trial [J]. Lancet,2007, 370:1764-1772.
4 Ronco, G., P. Giorgi-Rossi, F. Carozzi, et al. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test [J]. J Natl Cancer Inst,2008,100: 492-501.
5 Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data [J]. BMJ.2009, 339:b2968.
6 Bouvard V, Baan R, Straif K, et al. A review of human carcinogens—part B:biological agents [J]. Lancet Oncol,2009,10:321-2.
1 Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide [J]. J Pathol,1999,189:12-9.
2 Bosch FX, Lorincz A, Munoz N, et al. The causal relation between human papillomavirus and cervical cancer [J]. J Clin Pathol,2002,55:244-65.
3 Bosch FX, de Sanjose S. The epidemiology of human papillomavirus infection and cervical cancer [J]. Dis Markers,2007,23(4):213-27.
4武明辉,张淞文,张为远,等.2007-2008年北京地区25-54岁已婚妇女高危型人乳头瘤病毒感染的流行病学调查[J].中华妇产科杂志,2009,44(12)：892-897.
5 Wang CH, Garvilles RG, Chen CY. Characterization of human papillomavirus infection in north Taiwan [J]. J Med Virol,2010,82(8):1416-23.
6 Rui-fang Wu, Min Dai, You-lin Qiao. Human papillomavirus infection in women in Shenzhen City, People's Republic of China, a population typical of recent Chinese urbanization [J]. Int. J. Cancer,2007,121:1306-1311.
7 Martin-Hirsch PL, Wood NJ. Cervical cancer [J]. Clin Evid (Online),2011,27; pii: 0818.
8 Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions:a meta-analysis update [J]. Int J Cancer,2007,121(3):621-32.
9 Bulkmans, N. W., J. Berkhof, L. Rozendaal, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neo-plasia grade 3 and cancer:5-year follow-up of a randomised controlled implementation trial [J]. Lancet,2007, 370:1764-1772.
10 Ronco, G, P. Giorgi-Rossi, F. Carozzi, et al. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test [J]. J. Natl. Cancer Inst,2008,100: 492-501.
11 Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data [J]. BMJ,2009, 339:b2968.
12蒋明军,王书崎,龚向东.等.尖锐湿疣皮损中人乳头瘤病毒基因分型研究[J].中华皮肤科杂志,2005,38(5)；262-264.
13赵俊郁,岳学苹，王爱平.474例尖锐湿疣患者HPV检测与分型[J].中国麻风皮肤病杂志,2007,23(1);80.
14袁定芬,邓辉,丁徐安,尖锐湿疣HPV的分型及宫颈阴道脱落细胞和疣纠织中 HPV检测的比较[J].中国麻风皮肤病杂志,2008,24(10)；773-776.
15 Friis S, Kjaer SK, Frisch M, et al. Cervical intraepithelial neoplasia, anogenital cancer, and other cancer types in women after hospitalization for condylomata acuminata [J]. J Infect Dis,1997; 175:743-8.
16 Nordenvall C, Chang ET, Adami HO, et al. Cancer risk among patients with condylomata acuminata [J]. Int J Cancer,2006;119:888-93.
17 Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection [J]. Vaccine,2006,30; 24 Suppl 1:S1-15.
18 Carozzi, F. M., A. Del Mistro, M. Confortini, et al. Repro ducibility of HPV DNA testing by Hybrid Capture 2 in a screening setting [J]. Am. J. Clin. Pathol,2005,124: 716-721.
19 Cuzick, J., C. Clavel, K. U. Petry, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening [J]. Int. J. Cancer, 2006.119:1095-1101.
20 Ronco, G., P. Giorgi-Rossi, F. Carozzi, et al. Human papillo-mavirus testing and liquid-based cytology in primary screening of women younger than 35 years:results at recruitment for a randomised controlled trial [J]. Lancet Oncol,2006,7:547-555.
21 Jean-Luc Pretet, Veronique Dalstein, Sylvain Monnier-Benoit, et al. High risk HPV load estimated by Hybrid Capture Ⅱ(?) correlates with HPV 16 load measured by real-time PCR in cervical smears of HPV16-infected women [J]. Journal of Clinical Virology, 2004,31:140-147.
22 Dalstein V, Riethmuller D, Pretet JL, et al. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions:a longitudinal French cohort study [J]. Int J Cancer,2003,106(3):396-403.
23 Young-Tak Kim, Jong Min Lee, Soo-Young Hur, et al. Clearance of human papillomavirus infection after successful conization in patients with cervical intraepithelial neoplasia [J]. Int. J. Cancer,2010,126:1903-1909.
1 Fabrizio Ayala, Elena Grimaldi, Brunella Perfetto, et al.5-Aminolaevulinic acid and photodynamic therapy reduce IISV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatology, Photoimmunology & Photomedicine.2008,24; 237-243.
2 Jonathan P. Celli, Bryan Q. Spring, Imran Rizvi, et al. Imaging and photodymanic therapy:mechanisms, monitoring and optimization [J]. Chem Rev,2010,110(5): 2795-2838.
3 B.W. Henderson, T.J. Dougherty. How does photodynamic therapy work? [J] Photochem Photobiol.1992,55:145-157.
4 K. Berg, P.K. Selbo, A. Weyergang, et al. Hogset Porphyrin-related photosensitizers for cancer imaging and therapeutic applications [J]. J Microsc,2005.218:133-147.
5 D.E. Dolmans, D. Fukumura, R.K. Jain. Photodynamic therapy for cancer [J]. Nat Rev Cancer,2003,3:380-387.
6 M. Niedre, M.S. Patterson, B.C. Wilson. Direct near-infrared luminescence detection of singlet oxygen generated by photodynamic therapy in cells in vitro and tissues in vivo [J]. Photochem Photobiol,2002,75:382-391.
7 J. Moan, K. Berg. The photodegradation of porphyrins in cells can be used to estimate the lifetime of singlet oxygen [J]. Photochem Photobiol,1991,53:549-553.
8 N.L. Oleinick, R.L. Morris, I. Belichenko. The role of apoptosis in response to photodynamic therapy:what, where, why. and how [J]. Photochem Photobiol Sci,2002, 1:1-21.
9 K. Berg, K. Madslien, J.C. Bommer, et al. Light induced relocalization of sulfonated meso-tetraphenylporphines in NHIK 3025 cells and effects of dose fractionation [J]. Photochem Photobiol,1991.53:203-210.
10 D. Kessel, M. Conley, M.G. Vicente, et al. Studies on the subcellular localization of the porphycene CPO [J]. Photochem Photobiol,2005,81:569-572.
11 D. Kessel. Relocalization of cationic porphyrins during photodynamic therapy [J]. Photochem Photobiol Sci,2002,1:837-840.
12 S. Marchal, A. Francois, D. Dumas, et al. Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells [J]. Br J Cancer,2007,96:944-951.
13 Margaret Stanley. Genital human papillomavirus infections-current and prospective therapies [J]. J Natl Cancer Inst Monogr,2003,31:117-24.
14 Harald aur Hausen. papillomaviruses and cancer:from basic studies to clinical application [J]. Nat Rev Cancer,2002 May,2(5):342-50.
15 Doorbar J. The papillomavirus life cycle [J]. J Clin Virol.2005 Mar;32 Suppl 1:S7-15.
16 McMurray HR, McCance DJ. Human papillomavirus type 16 E6 activates TERT gene transcription through induction of c-Myc and release of USF-mediated repression [J]. J Virol,2003,77(18):9852-61.
17 Thomas M, Banks L. Human papillomavirus E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types [J]. J Gen Virol,1990,80: 1513-7.
18 Meyerson M, Counter CM, Eaton EN, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization [J]. Cell, 1997,90(4):785-95.
19 Frauke Fehrmann, Laimonis A Laimins. Human papillomaviruses:targeting differentiating epithelial cells for malignant transformation [J].Oncogene.2003,22: 5201-5207.
20 Broker TR, Chow LJ, Chin MT, et al. A molecular portrait of human papillomavirus carcinogenesis [J]. Cancer Cells,1989,7(5); 197-208.
21晋红中,王家璧,王宏伟.宫颈鳞状细胞癌及尖锐湿疣中HPV 16-E6.HPV 16-E7蛋白的表达[J].临床皮肤科杂志,2001.4(30)；91-93.
22 Dong WL, Caldeira S, Sehr P, et al. Determination of the binding affinity of different human papillomavirus E7 protein for the tumour suppressor pRb by a plate-bingding assay [J]. J Virol Methods,2001,98(1):91-8.
23 Hegde RS. The papillomavirus E2 proteins:structure, function and biology [J]. Annu Rev Biophys Biomol Struct,2002,31:343-60.
24 McBride AA, Romanczuk H, Howley PM. The papillomavirus E2 regulatory proteins [J]. J Biol Chem,1991,266(28):18411-4.
25 Stubenrauch F, Lim HB, Laimins LA. Differential requirements for conserved E2 binding sites in the life cycle of oncogenic human papillomavirus type 31 [J]. J Virol, 1998,72(2):1071-7.
26 Cahan, W. Cryosurgery of malignant and benign tumors [J]. Fed Proc,1965,24: S241-S248.
27 Cooper, I. S. Cryogenic surgery for cancer [J]. Fed Proc,1965,24:S237-S240.
28 Dutta. P., Montes. M., Gage, A. Experimental hepatic cryosurgery [J]. Cryobiology. 1977,14:596-608.
1 Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection [J]. Vaccine,2006,24(Suppl 1):S1-S15.
2 Ferlay JBF, Pisani P, Parkin DM. Globocan 2002, Cancer Incidence Mortality and Prevalence Worldwide IARC Cancerbase no.5. version 2.0 [M]. Lyon. France:IARC Press; 2004.
3 Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women [J]. N Engl J Med,1998,338:423-8.
4 Moscicki AB, Hills N. Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females [J]. JAMA,2001,285:2995-3002.
5 Franco EL, Villa LL. Sobrinho JP, et al. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer [J]. J Infect Dis,1999,180:1415-23.
6 Munoz N, Mendez F. Posso H, et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results [J]. J Infect Dis,2004.190:2077-87.
7 Goodman MT, Shvetsov YB, McDuffie K, et al. Prevalence, acquisition, and clearance of cervical human papillomavirus infection among women with normal cytology:Hawaii Human Papillomavirus Cohort Study [J]. Cancer Res,2008,68(21):8813-24.
8 Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer [J]. N Engl J Med,2003,348: 518-527.
9 Bouvard V, Baan R, Straif K, et al. A review of human carcinogens—part B:biological agents [J]. Lancet Oncol,2009,10:321-322.
10 Silvia de Sanjose, Wim G V Quint. Laia Alemany, et al. Human papillomavirus genotype attribution in invasive cervical cancer:a retrospective cross-sectional worldwide study [J]. Lancet Oncol.2010,11:1048-56.
11 Susanne K. Kj(?)r, Kirsten Frederiksen, Christian Munk, et al. Long-term Absolute Risk of Cervical Intraepithelial Neoplasia Grade 3 or Worse Following Human Papillomavirus Infection:Role of Persistence [J]. J Natl Cancer Inst,2010,102: 1478-1488.
12 Bistoletti P, Zellbi A, Moreno-Lopez J, et al. Genital papillomavirus infection after treatment for cervical intraepithelial neoplasia (CIN) Ⅲ [J]. Cancer,1988,62(9):2056-9.
13 Zivadinovic R. Lilic G, Lilic V, Petric A, et al. Recurrence of cervical intraepithelial neoplasias with negative cone margins:risk factors [J]. J BUON,2011 Jul-Sep,16(3): 498-504.
14 Kyrgiou, M. et al. The up-to-date evidence on colposcopy practice and treatment of cervical intraepithelial neoplasia:the Cochrane colposcopy & cervical cytopathology collaborative group (C5 group) approach [J]. Cancer Treat,2006,32:516-523.
15 Kalliala.I., A. Anttila, E. Pukkala. et al. Risk of cervical and other cancers after treatment of cervical intraepithelial neoplasia:retrospective cohort study [J]. BMJ,2005, 331:1183-1185.
16 M. Kyrgiou.G. Valasoulis,C. Founta, et al. Clinical management of HPV-related disease of the lower genital tract [J]. Ann N Y Acad Sci,2010:57-68.
17 Moan J, Peng Q. An outline of the hundred-year history of PDT [J]. Anticancer Res, 2003,23(5A):3591-3600.
18 Moan J. On the diffusion length of singlet oxygen in cells and tissues [J]. J Photochem Photobiol B Biol,1990,6(3):343-347.
19 Blume JE, Oseroff AR. Aminolevulinic acid photodynamic therapy for skin cancers [J]. Dermatol Clin,2007,25(1):5-14.
20 Morton CA. Photodynamic therapy for nonmelanoma skin cancer-and more [J]? Arch Dermatol,2004,140(1):116-120.
21 N.L. Oleinick. R.L. Morris, I. Belichenko. The role of apoptosis in response to photodynamic therapy:what, where, why, and how. Photochem [J]. Photobiol Sci,2002, 1:1-21.
22 Nucci V, Torchia D. Cappugi P. Treatment of anogenital condylomata acuminata with topical photodynamic therapy:report of 14 cases and review [J]. Int J Infect Dis,2010, 14 Suppl 3:e280-2.
23 Zhao B, He YY Recent advances in the prevention and treatment of skin cancer using photodynamic therapy [J]. Expert Rev Anticancer Ther,2010,10(11):1797-809.
24 Ayala F, Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24(5):237-43.
25 K. Berg, K. Madslien, J.C. Bommer, et al. Light induced relocalization of sulfonated meso-tetraphenylporphines in NHIK 3025 cells and effects of dose fractionation [J]. Photochem Photobiol,1991,53:203-210.
26 D. Kessel, M. Conley, M.G. Vicente, et al. Studies on the subcellular localization of the porphycene CPO [J]. Photochem Photobiol,2005,81:569-572.
27 D. Kessel. Relocalization of cationic porphyrins during photodynamic therapy [J]. Photochem Photobiol Sci,2002,1:837-840.
28 S. Marchal, A. Francois, D. Dumas, et al.Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells [J]. Br J Cancer,2007, 96:944-951.
1. Arima Y, Winer RL, Feng Q, et al. Development of genital warts after incident detection of human papillomavirus infection in young men [J]. J Infect Dis,2010,202: 1181-1184.
2. Stanley M. Genital Human Papillomavirus Infections—Current and Prospective Therapies [J]. J Natl Canc Inst Monogr,2003,31:117-124.
3. Jablonska S. Traditional therapies for the treatment of condylomata acuminata (genital warts) [J]. Australas J Dermatol,1998,39:S2-S4.
4. Wang HW, Wang XL, Zhang LL, et al. Aminolevulinic acid (ALA)-assisted photodynamic diagnosis of subclinical and latent HPV infection of external genital region [J]. Photodiagnosis Photodyn Ther,2008,5:251-255.
5. Rosemberg SK. Subclinical papilloma viral infection of male genitalia [J]. Urology, 1985,26:554-557.
6. Ross EV. Romero R, Kollias N, et al. Selectivity of protoporphyrin IX fluorescence for condylomata after topical application of 5-aminolevulinic acid:implications for photodynamic treatment [J]. Br J Dermatol,1997,137:736-742.
7. Chen K, Chang BZ, Ju M, et al. Comparative study of photodynamic therapy vs. CO2 laser vaporization in treatment of condylomata acuminata, a randomized clinical trial [J]. Br J Dermato,2007,156:516-520.
8. Juzeniene A, Juzenas P, Moan J. Application of 5-aminolevulinic acid and its derivatives for photodynamic therapy in vitro and in vivo [M]. In Gomer CJ, ed. Photodynamic therapy, methods in molecular biology New York:Springer Science 1 Business Media,2010; 97-106.
9. Forster B, Klein A, Szeimies RM, et al. Penetration enhancement of two topical 5-aminolaevulinic acid formulations for photodynamic therapy by erbium:YAG laser ablation of the stratum corneum: continuous versus fractional ablation [J]. Exp Dermatol, 2010,19:806-812.
10. McClean H, Shann S. A cross-sectional survey of treatment choices for anogenital warts [J]. Int J STD AIDS,2005,16:212-216.
11. Scheinfeld N., Lehman DS. An evidence-based review of medical and surgical treatments of genital warts [J]. Dermatol Online J,2006,12:5.
12. Freiman A. Nathaniel Bouganim. History of cryotherapy [J]. Dermatol Online J.2005, 11:9.
13. Allington HV. Liquid nitrogen in the treatment of skin diseases [J]. Calif Med.1950, 72:153-155.
14. Pirotta MV, Stein AN. Fairley CK, et al. Patterns of treatment of external genital warts in Australian sexual health clinics [J]. Sex Transm Dis,2009,36:375-379.
15. Liang J, Lu XN, Tang H. et al. Evaluation of photodynamic therapy using topical aminolevulinic acid hydrochloride in the treatment of condylomata acuminata:a comparative, randomized clinical trial [J]. Photodermatol Photoimmunol Photomed, 2009,25:293-297.
16. Wang XL, Wang HW, Wang HS, et al, Hillemanns P. Topical 5-aminolaevulinic acid-photodynamic therapy for the treatment of urethral condylomata acuminata [J]. Br J Dermatol,2004,151:880-885.
17. Ayala F, Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24:237-243.
18. Rossi R, Bruscino N. Ricceri F. et al. Photodynamic treatment for viral infections of the skin [J]. G Ital Dermatol Venereol,2009,144:79-83.
19. Prignano F, Lotti T, Spallanzani A, et al. Sequential effects of photodynamic treatment of basal cell carcinoma [J]. J Cutan Pathol,2009,36:409-416.
20. Morrow DI, Garland MJ. McCarron PA, et al. Innovative drug delivery strategies for topical photodynamic therapy using porphyrin precursors [J]. J Environ Pathol Toxicol, 2007,26:105-116.
21. Donnelly RF, McCarron PA, Morro DI, et al. Photosensitiser delivery for photodynamic therapy. Part 1:topical carrier platforms [J]. Expert Opin Drug Deliv,2008, 5:757-766.
22. Cahan W. Cryosurgery of malignant and benign tumors [J]. Fed Proc,1965,24: S241-S248.
23. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery [J]. Cryobiology,1998, 37:171-186.
24. D'Ambrogio A, Yerly S, Sahli R, et al. Human papilloma virus type and recurrence rate after surgical clearance of anal condylomata acuminate [J]. Sex Transm Dis,2009, 36:536-540.
25. Schlappner OLA, Shaffer EA. Anorectal condylomata acuminata:a missed part of the condyloma spectrum [J]. Can Med Assoc J,1978,118:172-173.
26. Liu YX, Zheng HY, Liu XR.5-aminolaevulinic acid-photodynamic therapy for the treatment of cervical condylomata acuminate [J]. Chin Med Sci J,2009,24:151-155.
27. Szeimies RM, Schleyer V, Moll I, et al. Adjuvant photodynamic therapy does not prevent recurrence of condylomata acuminata after carbon dioxide laser ablationFA phase Ⅲ, prospective, randomized, bicentric, double-blind study [J]. Dermatol Surg, 2009,35:757-764.
1 Hughes FJ, Romano MA. E1 protein of human papillomavirus is a DNA helicase/ATPase [J]. Nucleic Acids Res,1993,21(25):5817-23.
2 Conger KL, Liu JS, Kuo SR, et al. Human papillomavirus DNA replication. Interactions between the viral E1 protein and two subunits of human dna polymerase alpha/primase [J]. J Biol Chem,1999,274(5):2696-705.
3 Masterson PJ, Stanley MA, Lewis AP, et al. A C-terminal helicase domain of the human papillomavirus E1 protein binds E2 and the DNA polymerase alpha-primase p68 subunit [J].J Virol,1998,72(9):7407-19.
4 Demeret C, Desaintes C, Yaniv M, et al. Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes [J].J Virol,1997,71(12):9343-9.
5 Harald aur Hausen. papillomaviruses and cancer:from basic studies to clinical application [J]. Nat Rev Cancer.2002 May;2(5):342-50.
6 Frauke Fehrmann, Laimonis A Laimins. Human papillomaviruses:targeting differentiating epithelial cells for malignant transformation [J]. Oncogene.2003;22: 5201-5207.
7 Stanley MA, Browne HM, Appleby M, et al. Properties of a non-tumorigenic human cervical keratinocyte cell line [J]. Int J Cancer,1989,43(4):672-6.
8 Pett MR, Herdman MT, Palmer RD, et al. Selection of cervical keratinocytes containing integrated HPV16 associates with episome loss and an endogenous antiviral response [J]. Proc Natl Acad Sci U S A.2006 Mar 7;103(10):3822-7.
9 Braun L, Mikumo R, Mark HF, et al. Analysis of the growth properties and physical state of the human papillomavirus type 16 genome in cell lines derived from primary cervical tumors [J]. Am J Pathol,1993,143(3):832-44.
10 Frauke Fehrmann, Laimonis A Laimins. Human papillomaviruses:targeting differentiating epithelial cells for malignant transformation [J].Oncogene,2003;22: 5201-5207.
11 Harald aur Hausen. papillomaviruses and cancer:from basic studies to clinical application [J]. Nat Rev Cancer.2002 May;2(5):342-50.
12 Frattini MG, Lim HB, Laimins LA. In vitro synthesis of oncogenic human papillomaviruses requires episomal genomes for differentiation-dependent late expression [J]. Proc Natl Acad Sci USA,1996,93(7):3062-7.
13欧阳山鹰,何祖根,么崇正,等.人膀胱移行细胞癌细胞系PUMC—91的建立及其EGF受体检测[J].中华泌尿外科杂志,1994,15(2)：104.
14 HE Zu-gen, ZHENG Shan, LIU Hai-tao. et al. Detection of human papillomavirus-18 DNA in transitional cell carcinoma cell line of PUMC-91 [J]. The Practical Journal of Cancer,2001,16:225-227.
15 Del Vecchio AM, Romanczuk H, Howley PM, et al. Transient replication of human papillomavirus DNAs [J]. J Virol.1992 Oct;66(10):5949-58.
16 Xiao Yang, Wang Jun, YE Jingying, et al. Study on primary culture of juvenile onset recurrent respiratory papillomavirus cells. Chin Arch Otolaryngol Head Neck Surg [J]. 2006,13(9):629-632.
17 Chiang CM, G Dong, TR Broker, et al. Control of human papillomavirus type 11 origin of replication by the E2 family of transcription regulatory proteins [J]. J Virol, 1992,66:5224-31.
18 Chiang CM, Ustav M, Stenlund A, et al. Viral El and E2 proteins support replication of homologous and heterologous papillomaviral origins [J]. Proc Natl Acad Sci U S A. 1992,89(13):5799-803.
19 Remm M, R Brain, JR Jenkins. The E2 binding sites determine the efficiency of replication for the origin of human papillomavirus type 18 [J]. Nucleic Acids Res,1992, 20:6015-21.
20 Jelizaveta Geimanen, Helen Isok-Paas, Regina Pipitch, et al. Development of a cellular assay system to study the genome replication of high- and low- risk mucosal and cutaneous human papillomaviruses [J]. J Virol,2011,85(7):3315-29.
21 SHEN ZY, XU LY, LI EM, et al. The multistage process of carcinogenesis in human esophageal epithelial cells induced by human papillomavirus [J]. Oncol Rep,2004,11: 647-654.
22 CAO ZY, ZHAO J, LIAO QP, et al. Immotalization of human embryonic cervical epithelial cells induced by E6, E7 genes of human papillomavirus 16 [J]. Chinese Journal of Obstetrics and Gynecology,2004,39:486-488.
23 KE Zhao-yang, WU Zhan-yuan. Immortalization of human laryngeal epithelial cells induced by DNA of type 16 human papillomavirus [J]. China Journal of Modern Medicine,2008,18(14):1958-1963.
24 Federico De Marco, Marzia Perluigi, Cesira Foppoli, et al. UVB irradiation down-regulates HPV-16 RNA expression:implications for malignant progression of transformed cells [J]. Virus Res,2007,130(1-2):249-59.
25 Lee JH, Yi SM, Anderson ME, et al. Propagation of infectious human papillomavirus type 16 by using an adenovirus and Cre/LoxP mechanism [J]. Proc Natl Acad Sci USA, 2004,101(7):2094-9.
26 Boukamp P, Petrussevka RT, Breitkreutz D, et al. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line [J]. J Cell Biol,1988, 106:761-771.
27 Brune W, Durst M. Epithelial differentiation fails to support replication of cloned human papillomavirus type 16 DNA in transfected keratinocytes [J]. J Invest Dermatol, 1995,104(2):277-281.
28 Smith LH, Foster C, Hitchcock ME, et al. Titration of HPV-11 infectivity and antibody neutralization can be measured in vitro [J]. J Invest Dermatol,1995.105: 438-444.
29 Smith LH, Foster C, Hitchcock ME, et al. Titration of HPVol 1 infectivity and antibody neutralization can be measured in vitro [J]. J Invest Dermatol,1995,105(3): 438-44.
30 White WI, Wilson SD, Bonnez W, et al. In vitro infection and type restricted antibody mediated neutralization ofauthentic human papillomavirus type 16 [J]. J Virol,1998, 72(2):959-64.
31 Kreider JW, Howett MK, Wolfe SA, et al. Morphological transfoemation in vivo of human uterin cervix with papillomavirus from condylomata acuminate [J]. Nature,1985, 317(6038):639-41.
32 Kreider JW, Howett MK, Leure-Dupree AE, et al. Laboratory production in vivo of infectious human papillomavirus type 11 [J]. J Virol,1987,61(2):590-3.
33 Christensen ND. Kreider JW, Shah KV, et al. Detection of human serum antibodies that neutralize infectious human papillomavirus type 11 virions [J]. J Gen Virol,1992,73: 1261-7.
34 Christensen ND, Kreider JW, Cladel NM, et al. Monoclonal antibody-mediated neutralization of infectious human papillomavirus type 11 [J]. J Virol,1990,64(11): 5678-81.
35 Christensen ND, Kreider JW. Antibody-mediated neutralization in vivo of infectious papillomaviruses [J]. J Virol.1990,64(7):3151-6.
36 Sexton CJ, Williams AT, Topley P, et al. Development and characterization of a novel xenograft model permissive for human papillomavirus DNA amplification and late gene expression [J]. J Gen Virol.1995 Dec;76 (Pt 12):3107-12.
37 Bonnez w, DaRin C, Borkhuis C, et al. Isolation and propagation of human papillomavirus type 16 in human xenografts implanted in the severe combined immunodeficiency mouse [J]. J Virol,1998,72(6):5256-61.
38 Schoop VM, Mirancea N, Fusening NE. Epidermal organization and differentiation of HaCaT keratinocytes in organotypic coculture with human dermal fibroblasts [J]. J Invest Dermatol,1999,112:343-353.
39 Gniadecki R, Olszewska H, Gajkowska B. Changes in the ultrastructure of cytoskeleton and nuclear matrix during HaCaT keratinocyte differentiation [J]. Exp Dermatol,2001,10(2):71-79.
40 Meyers C, Frattilli MG, Hudson JB, et al. Biosynthesis of human papillomavirus from a continuous cell line upon epithelial differentiation [J]. Science,1992,257(5072): 971-973.
41 Dollard SC, Wilson A, Demeter LM, et al. Production of human papillomavirus and modulation of the infectious program in epithelial raR cultures [J]. Genes Dev,1992, 6(7):1131-42.
42 Meyers C, Mayer TJ, Ozbun MA. Synthesis of infectious human papillomavirus type 18 in differentiating epithelium transfected with viral DNA [J]. J Virol,1997,71(10): 7381-6.
43 Flores ER, Allen—Hoffann BL, Lee D, et al. Establishment of the human papillomavirus type 16 life cycle in an immortalized human forskin kdratinocyte cell line [J]. Virol,1999,262(2):344-354.
44 McLaughlin-Drubin ME, Christensen ND, Meyers C. Progagation, infectin and neutralization of authentic HPV16 virus [J]. Virology,2004,322(2):213-9.
45 McLaughlin-Drubin ME, Wilson S, Mullikin B, et al. Human papillomavirus type 45 propagation, infection and neutralization [J]. Virology,2003,312(1):1-7.
46 Ozbum MA. Infectious human papillomavims type 31b:purification and infection of an immortalized human keratinocyte cell line [J]. J Gen Virol,2002,83:2753-2763.
47 Mayers C, Bromberg-White JL, Zhang J, et al. Infectious virions produced from a human papillomavirus type 18/16 genomic DNA chimera [J]. J Virol,2002,76(10): 4723-33.
48 Fang L, Meyers C, Budgeon LR, et al. Induction of productive human papillomavirus type 11 life cycle in epithelial cells grown in organotypic raft cultures [J]. Virology.2006 Mar 30;347(1):28-35.
49 Delvenne P, Hubert P, Jacobs N, et al. The organotypic culture of HPV-transformaed keratinocytes:an effective in vitro model for the development of new immunotherapeutic approaches for mucosal preneoplastic lesions [J]. Vaccine,2001,19: 2557-64.
50 Baker TS, Newcomb WW, Olson NH, et al. Structures of bovine and human papillomavirus. Analysis by cryoelectron microscopy and three-dimensional image reconstruction [J]. Biophys J,1991.60(6):1445-56.
51 Belnap DM, Olson NH, Cladel NM, et al. Conserved features in papillomavirus and polyomavirus capsids [J]. J Mol Biol,1996,259(2):249-63.
52 Zhou J, Sun XY, Stenzel DJ, et al. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles [J]. Virology,1991,185:251-7.
53 Hagensee ME, Yaegashi N, Galloway DA. Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins [J]. J Virol,1993,67(1):315-22.
54 Rose RC, Bonnez W, Reichman RC, et al. Expression of human papillomavirus type 11 L1 protein in insect cells:in vivo and in vitro assembly of viruslike particles [J]. J Virol,1993.67(4):1936-44.
55 Kirnbauer R, Booy F. Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic [J]. Proc Natl Acad Sci,1992,89:12180-12.
56 Ochi H, Kondo K, Matsumoto K, et al. Neutralizing antibodies against human papillomavirus types 16,18,31,52, and 58 in serum samples from women in Japan with low-grade cervical intraepithelial neoplasia [J]. Clin Vaccine Immunol,2008, 15:1536-1540.
57 Muller M, Gissmann L, Cristiano RJ, et al. Papillomavirus capsid binding and uptake by cells from different tissues and species [J]. J Virol,1995,69(2):948-54.
58 Volpers C, Unckell F, Schirmacher P, et al. Binding and internalization of human papillomavirus type 33 virus-like particles by eukaryotic cells [J]. J Virol,1995,69(6): 3258-64.
59 Touze A, Courasget P. In vitro gene transfer using human papillomavirus-like particles [J]. Nucleic Acids Res,1998,26(5):1317-23.
60 Kawana K, Yoshikawa H, Taketani Y, et al. In vitro construction of pseudovirions of human papillomavirus type 16:incorporation of plasmic DNA into reassembled L1/L2 capsids [J]. J Virol,1998,72(12):10298-300.
61 Yeager MD, Aste-Amezaga M, Brown DR, et al. Neutralization of human papillomavirus pseudovirions:a novel and efficient approach to detect and characterize HPV neutralizing antibodies [J]. Virology,2000,278(2):570-7.
62 Bousarghin L, Combita-Rojas AL, Touze A, et al. Detection of neutralizing antibodies against human papillomavirus by inhibition of gene transfer mediated by HPV pseudovirions [J]. J Clin Microbiol,2002,40(3):926-32.
63 Unckell F, Streeck RE, Sapp M. Generation and neutralization of pseudovirions of human papillomavirus type 33 [J]. J Vriol,1997,71(4):2934-9.
64 Roden RB, Greenstone HL, Kirnbauer R, et al. In vitro generation and type-specific neutralization of human papillomavirus type 16 virion pseudotype [J]. J Virol,1996, 70(9):5875-83.
65 Rossi JL, Gissmann L, Jansen K, et al. Assembly of human papillomavirus type 16 pseudovirions in Saccharomyces cerevisiae [J]. Hum Gene Ther,2000,11(8):1165-76.
66 Angeletti PC, Kim K, Fernandes FJ, et al. Stable replication of papillomavirus genomes in Saccharomyces cerevisiae [J]. J Virol,2002,76(7):3350-8.
67 Zhao KN, Liu WJ, Frazer IH. Codon usage bias and A+T content variation in human papillomavirus genomes [J]. Virus Research,2003,98:95-104.
68 Zhou J, Liu WJ, Peng SW, et al. Papillomavirus capsid protein expression lever depends on the match between codon usage and tRNA availability [J]. J Virol,1999, 73(6):4972-82.
69 Pyeon D, Lambert PF, Ahlquist P. Production of infectious human papillomavirus independently of viral replication and epithelial cell differentiation [J]. Proc Natl Acad Sci USA,2005,102(26):9311-6.
70 Leder C, Kleinschmidt JA, Wiethe C, et al. Enhancement of capsid gene expression: preparing the human papillomavirus type 16 major structural gene L1 for DNA vaccination purposes [J]. J Virol.2001,75:9201-9.
71 Jacquet A, Magi M, Petry H, et al. High-level expression of recombinant house dust mite allergen Derp 1 in Picha pastoris [J]. Clin Allergy,2002,32:1048-1053.
72 Leder C, Kleinsehmidt J A, Wiethe C, et al. Enhancement of Capsid Gene Expression:Preparing the Human Papillomavirus type 16 Major Structural Gene L1 for DNA Vaccine Purposes [J]. J Virol,2001,75(19):9201-9209.
73李平川,张晓光,周玲,等.按酵母基因优化的HPV6型L1蛋白在大肠杆菌中高效表达[J].病毒学报,2004,20(3)：266-269.
74 Buck CB, Pastrana DV, Lowy DR, et al. Efficient intracellular assembly of papillomaviral vectors [J]. J Virol.2004 Jan;78(2):751-7.
75 Pyeon D, Lambert PF, Ahlquist P. Production of infectious human papillomavirus independently of viral replication and epithelial cell differentiation [J]. Proc Natl Acad Sci U S A.2005 Jun 28; 102(26):9311-6.
76王鹤,于继云,李力.稳定表达人乳头瘤病毒58型E6E7融合基因的B16细胞系的建立[J].中国免疫学杂志.2011,27(12)：1088-1092.
77赵蔚明,于修平,周亚滨.优化密码促进HPV 6b E7蛋白表达及DNA疫苗诱导 的细胞免疫反应[J].中华实验和临床病毒学杂志.2002,16(4)：309-311.
1 Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide [J]. J Pathol,1999,189:12-9.
2 Bosch FX, Lorincz A, Munoz N, et al. The causal relation between human papillomavirus and cervical cancer [J]. J Clin Pathol,2002,55:244-65.
3 Bosch FX, de Sanjose S. The epidemiology of human papillomavirus infection and cervical cancer [J]. Dis Markers,2007,23(4):213-27.
4 Kimbauer R. Booy. F'Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus—like particles that are highly immunogenic [J]. Proc Natl Acad Sci U S A,1992,89(24):12180-4.
5 Hagensee ME, Yaegashi N, Galloway DA. Self-assembly ofhuman papillomavirus type 1 capsids by expression of the LI protein alone or by coexpression of the LI and L2 capsid proteins [J]. J Virol,1993,67(1):315-22.
6 Rose RC, Bonnez w. Reichman RC, et al. Expression of human papillomavirus type 1 1 L1 protein in insect cells:in vivo and in vitro assembly of viruslike particles [J]. J Virol, 1993,67(4):1936-44.
7 Sasagawa T, Pushko P. Steers G, et al. Synthesis and assembly ofvirus-like particles of human papillomaviruses type 6 and type 16 in fission yeast Schizosaccharomyces pombe [J]. Virology,1995,206(1):126-35.
8 Zhou J, Sun XY, Stenzel DJ, et al. Expression of vaecinia recombinant HPV 16 LI and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles [J]. Virology,1991,185(1):251-7.
9 Christensen ND, Kimbauer R, Schiller JT, et al. Human papillomavirus types 6 and 11 have antigenically distinct strongly immunogenic conformationally dependent neutralizing epitopes [J]. Virology,1994.205(1):329-35.
10 Zhou J, Sun XY, Stenzel DJ, et al. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles [J]. Virology,1991,185:251-7.
11 Kirnbauer R, Booy F, Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic [J]. Proc Natl Acad Sci,1992,89:12180-12.
12 Ochi H, Kondo K, Matsumoto K. et al. Neutralizing antibodies against human papillomavirus types 16,18,31.52, and 58 in serum samples from women in Japan with low-grade cervical intraepithelial neoplasia [J]. Clin Vaccine Immunol,2008. 15:1536-1540.
13 Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine [J]. N Engl J Med,2002,347:1645-51.
14 Harro CD, Pang YY, Roden RB, et al. Salty and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine [J]. J Natl Cancer Inst.2001,93(4):284-92.
15 Pastrana DV, Vass WC, Lowy DR, et al. NHPV16 VLP vaccine induces human antibodies that neutralize divergent variants ofHPV16 [J]. Virology,2001,279(1):361-9.
16 Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective [J]. Int J Cancer,2004, 111(2):278-85.
17 Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6,11,16, and 18) L1 virus-like particle vaccine in young women:a randomised doubleblind placebo-controlled multicentre phase II efficacy trial [J]. Lancet Oncol,2005, 6:271-8.
18 The FUTURE II Study Group. Effect of prophylactic human papollomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3 and adenocarcinoma in situ:a combined analysis of four randomized clinical trials [J]. Lancet,2007,369:1861-8.
19 Pomfret TC, Gagnon JM Jr, Gilchrist AT. Quadrivalent human papillomavirus (HPV) vaccine:a review of safety, efficacy, and pharmacoeconomics [J]. J Clin Pharm Ther, 2011,36(1):1-9.
20 Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial [J]. Lancet,2006,367:1247-55.
21 Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years ofa bivalent L1 irus-like particle vaccine against human papillomavirus types 16 and 18: follow—up from a randomised control trial [J]. Lancet,2006,367(9518):1247-55,
22 Johnson KM, Kines RC, Roberts JN, et al. Role of heparan sulfate in attachment to and infection of the murine female genital tract by human papillomavirus [J]. J Virol, 2009,83(5):2067-74.
23 Buck CB, Thompson CD, Roberts JN, et al. Carrageenan is a potent inhibitor of papillomavirus infection [J]. PLoS Pathog,2006,2:69.
24 Rusnati M, Oreste P, Zoppetti G, et al. Biotechnological engineering of heparin/heparan sulphate:a novel area of multi-target drug discovery [J]. Curr Pharm Des,2005,11:2489-99.
25 David Lembo, Manuela Donalisio, Marco Rusnati, et al. Sulfated K5 Escherichia coli Polysaccharide Derivatives as Wide-Range Inhibitors of Genital Types of Human Papillomavirus [J]. Antimicrob Agents Chemother,2008,52(4):1374-81.
26 Donalisio M, Rusnati M, Civra A, et al. Identification of a dendrimeric heparan sulfate-binding peptide that inhibits infectivity of genital types of human papillomaviruses [J]. Antimicrob Agents Chemother,2010,54(10):4290-9.
27 Ross EV, Romero R, Kollias N, et al. Selectivity of protoporphyrin IX fluorescence for condylomata after topical application of 5-aminolevulinic acid:implications for photodynamic treatment [J]. Br J Dermatol,1997,137:736-42.
28 Ayala F, Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24(5):237-43.
29 K. Berg, K. Madslien, J.C. Bommer, R. Oftebro, J.W. Winkelman, J. Moan. Light induced relocalization of sulfonated meso-tetraphenylporphines in NHIK 3025 cells and effects of dose fractionation [J]. Photochem. Photobiol.,53 (1991), pp.203-210
30 D. Kessel, M. Conley, M.G. Vicente, J.J. Reiners. Studies on the subcellular localization of the porphycene CPO [J]. Photochem. Photobiol.,81 (2005). pp.569-572
31 D. Kessel. Relocalization of cationic porphyrins during photodynamic therapy.Photochem. Photobiol [J]. Sci.,1 (2002), pp.837-840
32 S. Marchal. A. Francois, D. Dumas, F. Guillemin, L. Bezdetnaya.Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells [J]. Br. J. Cancer,96 (2007), pp.944-951
33 Asta Juzeniene, Petras Juzenas, Johan Moan. Application of 5-Aminolevulinic Acid and Its Derivatives for Photodynamic Therapy In Vitro and In Vivo. In C.J. Gomer, ed. Photodynamic Therapy, Methods in Molecular Biology [J]. Springer Science+Business Media,2010:97-106.
34 Morrow DI, Garland MJ, McCarron PA, et al. Innovative drug delivery strategies for topical photodynamic therapy using porphyrin precursors [J]. J Environ Pathol Toxicol, 2007,26:105-116.
35 Donnelly, McCarron, Morro, et al. Photosensitiser delivery for photodynamic therapy. Part 1:topical carrier platforms [J]. Expert Opin Drug Deliv,2008,5:757-766.
36 Moore RA, Santos EB. Nicholls PK, et al. Intraepithelial DNA immunisation with a plasmid encoding a codon optimised COPV El gene sequence but not the wild type gene sequence completely protects against mucosal challenge with infectious COPV in beagles [J]. Virology,2002,304:451-9
37 Klencke B, Matijevic M, Urban RG, et al. Encapsulated plasmid DNA treatment for human papillomavirus 16-associated anal dysplasia:a phase Ⅰ study of ZYC101 [J]. Clin Cancer Res,2002,8:1028-37.
38 Chien-Fu Hung. Barbara Ma, Archana Monie, et al. Therapeutic human papillomavirus vaccines:current clinical trials and future directions [J]. Expert Opin BiolTher.2008,8(4):421-39.
39 Feltkamp MC, Smits HL, Vierboom MP,et al. Vaccination with cytotoxic T lymphocyte epitope-eontaining peptide protects against a tumor induced by human papillomavirus type 16-transformed cells [J]. Eur J Immunol,1993,23(9):2242-9.
40 teller MA, Gurski KJ, Murakami M, et al. Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirustype 16 E7 [J]. ClinCancerRes,1998,4(9):2103-9.
41 Muderspach L, Wilczynski S, Roman L. et al. A phase Ⅰ trial of a human papillomavirus(HPV) pepfide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV16 positive [J]. ClinCancerRes,2000,6(9):3406-16.
42 Hiranuma K, Tamaki S, Nishimura Y, et al. Helper T cell determinant peptide contributes to induction ofcellular immune responses by peptide vaccines against hepatitis C virus [J]. J Gen Virol,1999,80(Pt 1):187-93.
43 Bristol JA, Orsini C, Lindinger P, et al. Identification of a ras oncogene peptide that contains both CIM(+)and CD8(+)T cell epitopes in a nested configuration and elicits both T cell subset responses by peptide or DNAimmunization [J]. Cell Immunol,2000, 205(2):73-83.
44 Zwaveling S, Ferreira Mota SC, Nouta J, et al. Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides [J]. J Immunol,2002,169(1):350-8.
45 Thompson HS, Davies ML, WaRs MJ, et al. Enhanced immunogenicity of a recombinant genital warts vaccine adjuvanted with monophosphoryl lipid A [J]. Vaccine, 1998,16(20):1993-9.
46 Daflarian P, Mansour M, Benoit AC, et al. Eradication of established HPV 16 expressing tumors by a single administration of a vaccine composed of a liposome—encapsulated CTL-T helper fusion peptide in a water-in oil emulsion [J]. Vaccine,2006.
47 Boursnell ME, Rutherford E. Hiekling JK, et al. Construction and characterisation of a recombinant vaccinia virus expressing human papillomavirus proteins for immunotherapy of cervical cancer [J]. Vaccine.1996,14(16):1485-94.
48 Brandsma, Shlyankevich M, Zhang L, et al. Vaccination of rabbits with an adenovirus vector expressing the papillomavirus E2 protein leads to clearance of papillomas and infection [J]. J Virol,2004,78(1):116-23.
49 Garcia-Hemandez E, Gonzalez-Sanchez JL, Andrade-Manzano A, et al. Regression of papilloma hig}1-grade lesions(CIN 2 and CIN 3)is stimulated by therapeutic vaccination with MVA E2 recombinant vaccine [J]. Cancer Gene Ther,2006.
50 Reyes-Gutierrez P, Alvarez-Salas LM. Cleavage of HPV-16 E6/E7 mRNA mediated by modified 10-23 deoxyribozymes [J]. Oligonucleotides,2009.19(3):233-42.
51 W Gul, E Paynel, S Sun, et al. Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs [J]. Cancer Gene Therapy,2010,1-9.
52 Dymalla S, Scheffner M, Weber E, et al. A novel peptide motif binding to and blocking the intracellular activity of the human papillomavirus E6 oncoprotein [J]. J Mol Med,2009,87(3):321-31.
53 Wierzbicka M, Jackowska J, Bartochowska A, et al. Effectiveness of cidofovir intralesional treatment in recurrent respiratory papillomatosis [J]. Eur Arch Otorhinolaryngol,2011 Apr 26. [Epub ahead of print]
54 Donne AJ, Hampson L, He XT, et al. Cidofovir induces an increase in levels of low-risk and high-risk HPV E6 [J]. Head Neck,2009,31:893-901.
55 G.P Talwar, Sajad A Dar, Mahendra K Rai, et al. A novel polyherbal microbicide with inhibitory effect on bacterial, fungal and viral genital pathogens [J]. International Journal of Antimicrobial Agents,2008,32:180-185.
2 Brown DR, Schroeder JM, Bryan JT, et al. Detection of multiple human papillomavirus types in condylomata acuminata lesions from otherwise healthy and immunosuppressed patients [J]. J Clin Microbiol,1999,37:3316-22.
3 Friis S, Kjaer SK, Frisch M, et al. Cervical intraepithelial neoplasia, anogenital cancer, and other cancer types in women after hospitalization for condylomata acuminata [J]. J Infect Dis,1997,175:743-8.
4 Nordenvall C, Chang ET, Adami HO, et al. Cancer risk among patients with condylomata acuminata [J]. Int J Cancer,2006,119:888-93.
5 Ayala F, Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24:237-243.
6 Rossi R, Bruscino N, Ricceri F, Grazzini M, Dindelli M, Lotti T. Photodynamic treatment for viral infections of the skin [J]. G Ital Dermatol Venereol.2009,144:79-83.
7 Prignano F, Lotti T, Spallanzani A, Berti S, de Giorgi V, Moretti S. Sequential effects of photodynamic treatment of basal cell carcinoma [J]. J Cutan Pathol,2009,36:409-416.
1 Ross EV, Romero R, Kollias N, et al. Selectivity of protoporphyrin IX fluorescence for condylomata after topical application of 5-aminolevulinic acid:implications for photodynamic treatment [J]. Br J Dermatol,1997,137:736-42.
2 Ayala F. Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24(5):237-43.
3 Bulkmans, N. W., J. Berkhof, L. Rozendaal, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neo-plasia grade 3 and cancer:5-year follow-up of a randomised controlled implementation trial [J]. Lancet,2007, 370:1764-1772.
4 Ronco, G., P. Giorgi-Rossi, F. Carozzi, et al. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test [J]. J Natl Cancer Inst,2008,100: 492-501.
5 Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data [J]. BMJ.2009, 339:b2968.
6 Bouvard V, Baan R, Straif K, et al. A review of human carcinogens—part B:biological agents [J]. Lancet Oncol,2009,10:321-2.
1 Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide [J]. J Pathol,1999,189:12-9.
2 Bosch FX, Lorincz A, Munoz N, et al. The causal relation between human papillomavirus and cervical cancer [J]. J Clin Pathol,2002,55:244-65.
3 Bosch FX, de Sanjose S. The epidemiology of human papillomavirus infection and cervical cancer [J]. Dis Markers,2007,23(4):213-27.
4武明辉,张淞文,张为远,等.2007-2008年北京地区25-54岁已婚妇女高危型人乳头瘤病毒感染的流行病学调查[J].中华妇产科杂志,2009,44(12)：892-897.
5 Wang CH, Garvilles RG, Chen CY. Characterization of human papillomavirus infection in north Taiwan [J]. J Med Virol,2010,82(8):1416-23.
6 Rui-fang Wu, Min Dai, You-lin Qiao. Human papillomavirus infection in women in Shenzhen City, People's Republic of China, a population typical of recent Chinese urbanization [J]. Int. J. Cancer,2007,121:1306-1311.
7 Martin-Hirsch PL, Wood NJ. Cervical cancer [J]. Clin Evid (Online),2011,27; pii: 0818.
8 Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions:a meta-analysis update [J]. Int J Cancer,2007,121(3):621-32.
9 Bulkmans, N. W., J. Berkhof, L. Rozendaal, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neo-plasia grade 3 and cancer:5-year follow-up of a randomised controlled implementation trial [J]. Lancet,2007, 370:1764-1772.
10 Ronco, G, P. Giorgi-Rossi, F. Carozzi, et al. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test [J]. J. Natl. Cancer Inst,2008,100: 492-501.
11 Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data [J]. BMJ,2009, 339:b2968.
12蒋明军,王书崎,龚向东.等.尖锐湿疣皮损中人乳头瘤病毒基因分型研究[J].中华皮肤科杂志,2005,38(5)；262-264.
13赵俊郁,岳学苹，王爱平.474例尖锐湿疣患者HPV检测与分型[J].中国麻风皮肤病杂志,2007,23(1);80.
14袁定芬,邓辉,丁徐安,尖锐湿疣HPV的分型及宫颈阴道脱落细胞和疣纠织中 HPV检测的比较[J].中国麻风皮肤病杂志,2008,24(10)；773-776.
15 Friis S, Kjaer SK, Frisch M, et al. Cervical intraepithelial neoplasia, anogenital cancer, and other cancer types in women after hospitalization for condylomata acuminata [J]. J Infect Dis,1997; 175:743-8.
16 Nordenvall C, Chang ET, Adami HO, et al. Cancer risk among patients with condylomata acuminata [J]. Int J Cancer,2006;119:888-93.
17 Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection [J]. Vaccine,2006,30; 24 Suppl 1:S1-15.
18 Carozzi, F. M., A. Del Mistro, M. Confortini, et al. Repro ducibility of HPV DNA testing by Hybrid Capture 2 in a screening setting [J]. Am. J. Clin. Pathol,2005,124: 716-721.
19 Cuzick, J., C. Clavel, K. U. Petry, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening [J]. Int. J. Cancer, 2006.119:1095-1101.
20 Ronco, G., P. Giorgi-Rossi, F. Carozzi, et al. Human papillo-mavirus testing and liquid-based cytology in primary screening of women younger than 35 years:results at recruitment for a randomised controlled trial [J]. Lancet Oncol,2006,7:547-555.
21 Jean-Luc Pretet, Veronique Dalstein, Sylvain Monnier-Benoit, et al. High risk HPV load estimated by Hybrid Capture Ⅱ(?) correlates with HPV 16 load measured by real-time PCR in cervical smears of HPV16-infected women [J]. Journal of Clinical Virology, 2004,31:140-147.
22 Dalstein V, Riethmuller D, Pretet JL, et al. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions:a longitudinal French cohort study [J]. Int J Cancer,2003,106(3):396-403.
23 Young-Tak Kim, Jong Min Lee, Soo-Young Hur, et al. Clearance of human papillomavirus infection after successful conization in patients with cervical intraepithelial neoplasia [J]. Int. J. Cancer,2010,126:1903-1909.
1 Fabrizio Ayala, Elena Grimaldi, Brunella Perfetto, et al.5-Aminolaevulinic acid and photodynamic therapy reduce IISV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatology, Photoimmunology & Photomedicine.2008,24; 237-243.
2 Jonathan P. Celli, Bryan Q. Spring, Imran Rizvi, et al. Imaging and photodymanic therapy:mechanisms, monitoring and optimization [J]. Chem Rev,2010,110(5): 2795-2838.
3 B.W. Henderson, T.J. Dougherty. How does photodynamic therapy work? [J] Photochem Photobiol.1992,55:145-157.
4 K. Berg, P.K. Selbo, A. Weyergang, et al. Hogset Porphyrin-related photosensitizers for cancer imaging and therapeutic applications [J]. J Microsc,2005.218:133-147.
5 D.E. Dolmans, D. Fukumura, R.K. Jain. Photodynamic therapy for cancer [J]. Nat Rev Cancer,2003,3:380-387.
6 M. Niedre, M.S. Patterson, B.C. Wilson. Direct near-infrared luminescence detection of singlet oxygen generated by photodynamic therapy in cells in vitro and tissues in vivo [J]. Photochem Photobiol,2002,75:382-391.
7 J. Moan, K. Berg. The photodegradation of porphyrins in cells can be used to estimate the lifetime of singlet oxygen [J]. Photochem Photobiol,1991,53:549-553.
8 N.L. Oleinick, R.L. Morris, I. Belichenko. The role of apoptosis in response to photodynamic therapy:what, where, why. and how [J]. Photochem Photobiol Sci,2002, 1:1-21.
9 K. Berg, K. Madslien, J.C. Bommer, et al. Light induced relocalization of sulfonated meso-tetraphenylporphines in NHIK 3025 cells and effects of dose fractionation [J]. Photochem Photobiol,1991.53:203-210.
10 D. Kessel, M. Conley, M.G. Vicente, et al. Studies on the subcellular localization of the porphycene CPO [J]. Photochem Photobiol,2005,81:569-572.
11 D. Kessel. Relocalization of cationic porphyrins during photodynamic therapy [J]. Photochem Photobiol Sci,2002,1:837-840.
12 S. Marchal, A. Francois, D. Dumas, et al. Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells [J]. Br J Cancer,2007,96:944-951.
13 Margaret Stanley. Genital human papillomavirus infections-current and prospective therapies [J]. J Natl Cancer Inst Monogr,2003,31:117-24.
14 Harald aur Hausen. papillomaviruses and cancer:from basic studies to clinical application [J]. Nat Rev Cancer,2002 May,2(5):342-50.
15 Doorbar J. The papillomavirus life cycle [J]. J Clin Virol.2005 Mar;32 Suppl 1:S7-15.
16 McMurray HR, McCance DJ. Human papillomavirus type 16 E6 activates TERT gene transcription through induction of c-Myc and release of USF-mediated repression [J]. J Virol,2003,77(18):9852-61.
17 Thomas M, Banks L. Human papillomavirus E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types [J]. J Gen Virol,1990,80: 1513-7.
18 Meyerson M, Counter CM, Eaton EN, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization [J]. Cell, 1997,90(4):785-95.
19 Frauke Fehrmann, Laimonis A Laimins. Human papillomaviruses:targeting differentiating epithelial cells for malignant transformation [J].Oncogene.2003,22: 5201-5207.
20 Broker TR, Chow LJ, Chin MT, et al. A molecular portrait of human papillomavirus carcinogenesis [J]. Cancer Cells,1989,7(5); 197-208.
21晋红中,王家璧,王宏伟.宫颈鳞状细胞癌及尖锐湿疣中HPV 16-E6.HPV 16-E7蛋白的表达[J].临床皮肤科杂志,2001.4(30)；91-93.
22 Dong WL, Caldeira S, Sehr P, et al. Determination of the binding affinity of different human papillomavirus E7 protein for the tumour suppressor pRb by a plate-bingding assay [J]. J Virol Methods,2001,98(1):91-8.
23 Hegde RS. The papillomavirus E2 proteins:structure, function and biology [J]. Annu Rev Biophys Biomol Struct,2002,31:343-60.
24 McBride AA, Romanczuk H, Howley PM. The papillomavirus E2 regulatory proteins [J]. J Biol Chem,1991,266(28):18411-4.
25 Stubenrauch F, Lim HB, Laimins LA. Differential requirements for conserved E2 binding sites in the life cycle of oncogenic human papillomavirus type 31 [J]. J Virol, 1998,72(2):1071-7.
26 Cahan, W. Cryosurgery of malignant and benign tumors [J]. Fed Proc,1965,24: S241-S248.
27 Cooper, I. S. Cryogenic surgery for cancer [J]. Fed Proc,1965,24:S237-S240.
28 Dutta. P., Montes. M., Gage, A. Experimental hepatic cryosurgery [J]. Cryobiology. 1977,14:596-608.
1 Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection [J]. Vaccine,2006,24(Suppl 1):S1-S15.
2 Ferlay JBF, Pisani P, Parkin DM. Globocan 2002, Cancer Incidence Mortality and Prevalence Worldwide IARC Cancerbase no.5. version 2.0 [M]. Lyon. France:IARC Press; 2004.
3 Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women [J]. N Engl J Med,1998,338:423-8.
4 Moscicki AB, Hills N. Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females [J]. JAMA,2001,285:2995-3002.
5 Franco EL, Villa LL. Sobrinho JP, et al. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer [J]. J Infect Dis,1999,180:1415-23.
6 Munoz N, Mendez F. Posso H, et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results [J]. J Infect Dis,2004.190:2077-87.
7 Goodman MT, Shvetsov YB, McDuffie K, et al. Prevalence, acquisition, and clearance of cervical human papillomavirus infection among women with normal cytology:Hawaii Human Papillomavirus Cohort Study [J]. Cancer Res,2008,68(21):8813-24.
8 Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer [J]. N Engl J Med,2003,348: 518-527.
9 Bouvard V, Baan R, Straif K, et al. A review of human carcinogens—part B:biological agents [J]. Lancet Oncol,2009,10:321-322.
10 Silvia de Sanjose, Wim G V Quint. Laia Alemany, et al. Human papillomavirus genotype attribution in invasive cervical cancer:a retrospective cross-sectional worldwide study [J]. Lancet Oncol.2010,11:1048-56.
11 Susanne K. Kj(?)r, Kirsten Frederiksen, Christian Munk, et al. Long-term Absolute Risk of Cervical Intraepithelial Neoplasia Grade 3 or Worse Following Human Papillomavirus Infection:Role of Persistence [J]. J Natl Cancer Inst,2010,102: 1478-1488.
12 Bistoletti P, Zellbi A, Moreno-Lopez J, et al. Genital papillomavirus infection after treatment for cervical intraepithelial neoplasia (CIN) Ⅲ [J]. Cancer,1988,62(9):2056-9.
13 Zivadinovic R. Lilic G, Lilic V, Petric A, et al. Recurrence of cervical intraepithelial neoplasias with negative cone margins:risk factors [J]. J BUON,2011 Jul-Sep,16(3): 498-504.
14 Kyrgiou, M. et al. The up-to-date evidence on colposcopy practice and treatment of cervical intraepithelial neoplasia:the Cochrane colposcopy & cervical cytopathology collaborative group (C5 group) approach [J]. Cancer Treat,2006,32:516-523.
15 Kalliala.I., A. Anttila, E. Pukkala. et al. Risk of cervical and other cancers after treatment of cervical intraepithelial neoplasia:retrospective cohort study [J]. BMJ,2005, 331:1183-1185.
16 M. Kyrgiou.G. Valasoulis,C. Founta, et al. Clinical management of HPV-related disease of the lower genital tract [J]. Ann N Y Acad Sci,2010:57-68.
17 Moan J, Peng Q. An outline of the hundred-year history of PDT [J]. Anticancer Res, 2003,23(5A):3591-3600.
18 Moan J. On the diffusion length of singlet oxygen in cells and tissues [J]. J Photochem Photobiol B Biol,1990,6(3):343-347.
19 Blume JE, Oseroff AR. Aminolevulinic acid photodynamic therapy for skin cancers [J]. Dermatol Clin,2007,25(1):5-14.
20 Morton CA. Photodynamic therapy for nonmelanoma skin cancer-and more [J]? Arch Dermatol,2004,140(1):116-120.
21 N.L. Oleinick. R.L. Morris, I. Belichenko. The role of apoptosis in response to photodynamic therapy:what, where, why, and how. Photochem [J]. Photobiol Sci,2002, 1:1-21.
22 Nucci V, Torchia D. Cappugi P. Treatment of anogenital condylomata acuminata with topical photodynamic therapy:report of 14 cases and review [J]. Int J Infect Dis,2010, 14 Suppl 3:e280-2.
23 Zhao B, He YY Recent advances in the prevention and treatment of skin cancer using photodynamic therapy [J]. Expert Rev Anticancer Ther,2010,10(11):1797-809.
24 Ayala F, Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24(5):237-43.
25 K. Berg, K. Madslien, J.C. Bommer, et al. Light induced relocalization of sulfonated meso-tetraphenylporphines in NHIK 3025 cells and effects of dose fractionation [J]. Photochem Photobiol,1991,53:203-210.
26 D. Kessel, M. Conley, M.G. Vicente, et al. Studies on the subcellular localization of the porphycene CPO [J]. Photochem Photobiol,2005,81:569-572.
27 D. Kessel. Relocalization of cationic porphyrins during photodynamic therapy [J]. Photochem Photobiol Sci,2002,1:837-840.
28 S. Marchal, A. Francois, D. Dumas, et al.Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells [J]. Br J Cancer,2007, 96:944-951.
1. Arima Y, Winer RL, Feng Q, et al. Development of genital warts after incident detection of human papillomavirus infection in young men [J]. J Infect Dis,2010,202: 1181-1184.
2. Stanley M. Genital Human Papillomavirus Infections—Current and Prospective Therapies [J]. J Natl Canc Inst Monogr,2003,31:117-124.
3. Jablonska S. Traditional therapies for the treatment of condylomata acuminata (genital warts) [J]. Australas J Dermatol,1998,39:S2-S4.
4. Wang HW, Wang XL, Zhang LL, et al. Aminolevulinic acid (ALA)-assisted photodynamic diagnosis of subclinical and latent HPV infection of external genital region [J]. Photodiagnosis Photodyn Ther,2008,5:251-255.
5. Rosemberg SK. Subclinical papilloma viral infection of male genitalia [J]. Urology, 1985,26:554-557.
6. Ross EV. Romero R, Kollias N, et al. Selectivity of protoporphyrin IX fluorescence for condylomata after topical application of 5-aminolevulinic acid:implications for photodynamic treatment [J]. Br J Dermatol,1997,137:736-742.
7. Chen K, Chang BZ, Ju M, et al. Comparative study of photodynamic therapy vs. CO2 laser vaporization in treatment of condylomata acuminata, a randomized clinical trial [J]. Br J Dermato,2007,156:516-520.
8. Juzeniene A, Juzenas P, Moan J. Application of 5-aminolevulinic acid and its derivatives for photodynamic therapy in vitro and in vivo [M]. In Gomer CJ, ed. Photodynamic therapy, methods in molecular biology New York:Springer Science 1 Business Media,2010; 97-106.
9. Forster B, Klein A, Szeimies RM, et al. Penetration enhancement of two topical 5-aminolaevulinic acid formulations for photodynamic therapy by erbium:YAG laser ablation of the stratum corneum: continuous versus fractional ablation [J]. Exp Dermatol, 2010,19:806-812.
10. McClean H, Shann S. A cross-sectional survey of treatment choices for anogenital warts [J]. Int J STD AIDS,2005,16:212-216.
11. Scheinfeld N., Lehman DS. An evidence-based review of medical and surgical treatments of genital warts [J]. Dermatol Online J,2006,12:5.
12. Freiman A. Nathaniel Bouganim. History of cryotherapy [J]. Dermatol Online J.2005, 11:9.
13. Allington HV. Liquid nitrogen in the treatment of skin diseases [J]. Calif Med.1950, 72:153-155.
14. Pirotta MV, Stein AN. Fairley CK, et al. Patterns of treatment of external genital warts in Australian sexual health clinics [J]. Sex Transm Dis,2009,36:375-379.
15. Liang J, Lu XN, Tang H. et al. Evaluation of photodynamic therapy using topical aminolevulinic acid hydrochloride in the treatment of condylomata acuminata:a comparative, randomized clinical trial [J]. Photodermatol Photoimmunol Photomed, 2009,25:293-297.
16. Wang XL, Wang HW, Wang HS, et al, Hillemanns P. Topical 5-aminolaevulinic acid-photodynamic therapy for the treatment of urethral condylomata acuminata [J]. Br J Dermatol,2004,151:880-885.
17. Ayala F, Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24:237-243.
18. Rossi R, Bruscino N. Ricceri F. et al. Photodynamic treatment for viral infections of the skin [J]. G Ital Dermatol Venereol,2009,144:79-83.
19. Prignano F, Lotti T, Spallanzani A, et al. Sequential effects of photodynamic treatment of basal cell carcinoma [J]. J Cutan Pathol,2009,36:409-416.
20. Morrow DI, Garland MJ. McCarron PA, et al. Innovative drug delivery strategies for topical photodynamic therapy using porphyrin precursors [J]. J Environ Pathol Toxicol, 2007,26:105-116.
21. Donnelly RF, McCarron PA, Morro DI, et al. Photosensitiser delivery for photodynamic therapy. Part 1:topical carrier platforms [J]. Expert Opin Drug Deliv,2008, 5:757-766.
22. Cahan W. Cryosurgery of malignant and benign tumors [J]. Fed Proc,1965,24: S241-S248.
23. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery [J]. Cryobiology,1998, 37:171-186.
24. D'Ambrogio A, Yerly S, Sahli R, et al. Human papilloma virus type and recurrence rate after surgical clearance of anal condylomata acuminate [J]. Sex Transm Dis,2009, 36:536-540.
25. Schlappner OLA, Shaffer EA. Anorectal condylomata acuminata:a missed part of the condyloma spectrum [J]. Can Med Assoc J,1978,118:172-173.
26. Liu YX, Zheng HY, Liu XR.5-aminolaevulinic acid-photodynamic therapy for the treatment of cervical condylomata acuminate [J]. Chin Med Sci J,2009,24:151-155.
27. Szeimies RM, Schleyer V, Moll I, et al. Adjuvant photodynamic therapy does not prevent recurrence of condylomata acuminata after carbon dioxide laser ablationFA phase Ⅲ, prospective, randomized, bicentric, double-blind study [J]. Dermatol Surg, 2009,35:757-764.
1 Hughes FJ, Romano MA. E1 protein of human papillomavirus is a DNA helicase/ATPase [J]. Nucleic Acids Res,1993,21(25):5817-23.
2 Conger KL, Liu JS, Kuo SR, et al. Human papillomavirus DNA replication. Interactions between the viral E1 protein and two subunits of human dna polymerase alpha/primase [J]. J Biol Chem,1999,274(5):2696-705.
3 Masterson PJ, Stanley MA, Lewis AP, et al. A C-terminal helicase domain of the human papillomavirus E1 protein binds E2 and the DNA polymerase alpha-primase p68 subunit [J].J Virol,1998,72(9):7407-19.
4 Demeret C, Desaintes C, Yaniv M, et al. Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes [J].J Virol,1997,71(12):9343-9.
5 Harald aur Hausen. papillomaviruses and cancer:from basic studies to clinical application [J]. Nat Rev Cancer.2002 May;2(5):342-50.
6 Frauke Fehrmann, Laimonis A Laimins. Human papillomaviruses:targeting differentiating epithelial cells for malignant transformation [J]. Oncogene.2003;22: 5201-5207.
7 Stanley MA, Browne HM, Appleby M, et al. Properties of a non-tumorigenic human cervical keratinocyte cell line [J]. Int J Cancer,1989,43(4):672-6.
8 Pett MR, Herdman MT, Palmer RD, et al. Selection of cervical keratinocytes containing integrated HPV16 associates with episome loss and an endogenous antiviral response [J]. Proc Natl Acad Sci U S A.2006 Mar 7;103(10):3822-7.
9 Braun L, Mikumo R, Mark HF, et al. Analysis of the growth properties and physical state of the human papillomavirus type 16 genome in cell lines derived from primary cervical tumors [J]. Am J Pathol,1993,143(3):832-44.
10 Frauke Fehrmann, Laimonis A Laimins. Human papillomaviruses:targeting differentiating epithelial cells for malignant transformation [J].Oncogene,2003;22: 5201-5207.
11 Harald aur Hausen. papillomaviruses and cancer:from basic studies to clinical application [J]. Nat Rev Cancer.2002 May;2(5):342-50.
12 Frattini MG, Lim HB, Laimins LA. In vitro synthesis of oncogenic human papillomaviruses requires episomal genomes for differentiation-dependent late expression [J]. Proc Natl Acad Sci USA,1996,93(7):3062-7.
13欧阳山鹰,何祖根,么崇正,等.人膀胱移行细胞癌细胞系PUMC—91的建立及其EGF受体检测[J].中华泌尿外科杂志,1994,15(2)：104.
14 HE Zu-gen, ZHENG Shan, LIU Hai-tao. et al. Detection of human papillomavirus-18 DNA in transitional cell carcinoma cell line of PUMC-91 [J]. The Practical Journal of Cancer,2001,16:225-227.
15 Del Vecchio AM, Romanczuk H, Howley PM, et al. Transient replication of human papillomavirus DNAs [J]. J Virol.1992 Oct;66(10):5949-58.
16 Xiao Yang, Wang Jun, YE Jingying, et al. Study on primary culture of juvenile onset recurrent respiratory papillomavirus cells. Chin Arch Otolaryngol Head Neck Surg [J]. 2006,13(9):629-632.
17 Chiang CM, G Dong, TR Broker, et al. Control of human papillomavirus type 11 origin of replication by the E2 family of transcription regulatory proteins [J]. J Virol, 1992,66:5224-31.
18 Chiang CM, Ustav M, Stenlund A, et al. Viral El and E2 proteins support replication of homologous and heterologous papillomaviral origins [J]. Proc Natl Acad Sci U S A. 1992,89(13):5799-803.
19 Remm M, R Brain, JR Jenkins. The E2 binding sites determine the efficiency of replication for the origin of human papillomavirus type 18 [J]. Nucleic Acids Res,1992, 20:6015-21.
20 Jelizaveta Geimanen, Helen Isok-Paas, Regina Pipitch, et al. Development of a cellular assay system to study the genome replication of high- and low- risk mucosal and cutaneous human papillomaviruses [J]. J Virol,2011,85(7):3315-29.
21 SHEN ZY, XU LY, LI EM, et al. The multistage process of carcinogenesis in human esophageal epithelial cells induced by human papillomavirus [J]. Oncol Rep,2004,11: 647-654.
22 CAO ZY, ZHAO J, LIAO QP, et al. Immotalization of human embryonic cervical epithelial cells induced by E6, E7 genes of human papillomavirus 16 [J]. Chinese Journal of Obstetrics and Gynecology,2004,39:486-488.
23 KE Zhao-yang, WU Zhan-yuan. Immortalization of human laryngeal epithelial cells induced by DNA of type 16 human papillomavirus [J]. China Journal of Modern Medicine,2008,18(14):1958-1963.
24 Federico De Marco, Marzia Perluigi, Cesira Foppoli, et al. UVB irradiation down-regulates HPV-16 RNA expression:implications for malignant progression of transformed cells [J]. Virus Res,2007,130(1-2):249-59.
25 Lee JH, Yi SM, Anderson ME, et al. Propagation of infectious human papillomavirus type 16 by using an adenovirus and Cre/LoxP mechanism [J]. Proc Natl Acad Sci USA, 2004,101(7):2094-9.
26 Boukamp P, Petrussevka RT, Breitkreutz D, et al. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line [J]. J Cell Biol,1988, 106:761-771.
27 Brune W, Durst M. Epithelial differentiation fails to support replication of cloned human papillomavirus type 16 DNA in transfected keratinocytes [J]. J Invest Dermatol, 1995,104(2):277-281.
28 Smith LH, Foster C, Hitchcock ME, et al. Titration of HPV-11 infectivity and antibody neutralization can be measured in vitro [J]. J Invest Dermatol,1995.105: 438-444.
29 Smith LH, Foster C, Hitchcock ME, et al. Titration of HPVol 1 infectivity and antibody neutralization can be measured in vitro [J]. J Invest Dermatol,1995,105(3): 438-44.
30 White WI, Wilson SD, Bonnez W, et al. In vitro infection and type restricted antibody mediated neutralization ofauthentic human papillomavirus type 16 [J]. J Virol,1998, 72(2):959-64.
31 Kreider JW, Howett MK, Wolfe SA, et al. Morphological transfoemation in vivo of human uterin cervix with papillomavirus from condylomata acuminate [J]. Nature,1985, 317(6038):639-41.
32 Kreider JW, Howett MK, Leure-Dupree AE, et al. Laboratory production in vivo of infectious human papillomavirus type 11 [J]. J Virol,1987,61(2):590-3.
33 Christensen ND. Kreider JW, Shah KV, et al. Detection of human serum antibodies that neutralize infectious human papillomavirus type 11 virions [J]. J Gen Virol,1992,73: 1261-7.
34 Christensen ND, Kreider JW, Cladel NM, et al. Monoclonal antibody-mediated neutralization of infectious human papillomavirus type 11 [J]. J Virol,1990,64(11): 5678-81.
35 Christensen ND, Kreider JW. Antibody-mediated neutralization in vivo of infectious papillomaviruses [J]. J Virol.1990,64(7):3151-6.
36 Sexton CJ, Williams AT, Topley P, et al. Development and characterization of a novel xenograft model permissive for human papillomavirus DNA amplification and late gene expression [J]. J Gen Virol.1995 Dec;76 (Pt 12):3107-12.
37 Bonnez w, DaRin C, Borkhuis C, et al. Isolation and propagation of human papillomavirus type 16 in human xenografts implanted in the severe combined immunodeficiency mouse [J]. J Virol,1998,72(6):5256-61.
38 Schoop VM, Mirancea N, Fusening NE. Epidermal organization and differentiation of HaCaT keratinocytes in organotypic coculture with human dermal fibroblasts [J]. J Invest Dermatol,1999,112:343-353.
39 Gniadecki R, Olszewska H, Gajkowska B. Changes in the ultrastructure of cytoskeleton and nuclear matrix during HaCaT keratinocyte differentiation [J]. Exp Dermatol,2001,10(2):71-79.
40 Meyers C, Frattilli MG, Hudson JB, et al. Biosynthesis of human papillomavirus from a continuous cell line upon epithelial differentiation [J]. Science,1992,257(5072): 971-973.
41 Dollard SC, Wilson A, Demeter LM, et al. Production of human papillomavirus and modulation of the infectious program in epithelial raR cultures [J]. Genes Dev,1992, 6(7):1131-42.
42 Meyers C, Mayer TJ, Ozbun MA. Synthesis of infectious human papillomavirus type 18 in differentiating epithelium transfected with viral DNA [J]. J Virol,1997,71(10): 7381-6.
43 Flores ER, Allen—Hoffann BL, Lee D, et al. Establishment of the human papillomavirus type 16 life cycle in an immortalized human forskin kdratinocyte cell line [J]. Virol,1999,262(2):344-354.
44 McLaughlin-Drubin ME, Christensen ND, Meyers C. Progagation, infectin and neutralization of authentic HPV16 virus [J]. Virology,2004,322(2):213-9.
45 McLaughlin-Drubin ME, Wilson S, Mullikin B, et al. Human papillomavirus type 45 propagation, infection and neutralization [J]. Virology,2003,312(1):1-7.
46 Ozbum MA. Infectious human papillomavims type 31b:purification and infection of an immortalized human keratinocyte cell line [J]. J Gen Virol,2002,83:2753-2763.
47 Mayers C, Bromberg-White JL, Zhang J, et al. Infectious virions produced from a human papillomavirus type 18/16 genomic DNA chimera [J]. J Virol,2002,76(10): 4723-33.
48 Fang L, Meyers C, Budgeon LR, et al. Induction of productive human papillomavirus type 11 life cycle in epithelial cells grown in organotypic raft cultures [J]. Virology.2006 Mar 30;347(1):28-35.
49 Delvenne P, Hubert P, Jacobs N, et al. The organotypic culture of HPV-transformaed keratinocytes:an effective in vitro model for the development of new immunotherapeutic approaches for mucosal preneoplastic lesions [J]. Vaccine,2001,19: 2557-64.
50 Baker TS, Newcomb WW, Olson NH, et al. Structures of bovine and human papillomavirus. Analysis by cryoelectron microscopy and three-dimensional image reconstruction [J]. Biophys J,1991.60(6):1445-56.
51 Belnap DM, Olson NH, Cladel NM, et al. Conserved features in papillomavirus and polyomavirus capsids [J]. J Mol Biol,1996,259(2):249-63.
52 Zhou J, Sun XY, Stenzel DJ, et al. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles [J]. Virology,1991,185:251-7.
53 Hagensee ME, Yaegashi N, Galloway DA. Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins [J]. J Virol,1993,67(1):315-22.
54 Rose RC, Bonnez W, Reichman RC, et al. Expression of human papillomavirus type 11 L1 protein in insect cells:in vivo and in vitro assembly of viruslike particles [J]. J Virol,1993.67(4):1936-44.
55 Kirnbauer R, Booy F. Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic [J]. Proc Natl Acad Sci,1992,89:12180-12.
56 Ochi H, Kondo K, Matsumoto K, et al. Neutralizing antibodies against human papillomavirus types 16,18,31,52, and 58 in serum samples from women in Japan with low-grade cervical intraepithelial neoplasia [J]. Clin Vaccine Immunol,2008, 15:1536-1540.
57 Muller M, Gissmann L, Cristiano RJ, et al. Papillomavirus capsid binding and uptake by cells from different tissues and species [J]. J Virol,1995,69(2):948-54.
58 Volpers C, Unckell F, Schirmacher P, et al. Binding and internalization of human papillomavirus type 33 virus-like particles by eukaryotic cells [J]. J Virol,1995,69(6): 3258-64.
59 Touze A, Courasget P. In vitro gene transfer using human papillomavirus-like particles [J]. Nucleic Acids Res,1998,26(5):1317-23.
60 Kawana K, Yoshikawa H, Taketani Y, et al. In vitro construction of pseudovirions of human papillomavirus type 16:incorporation of plasmic DNA into reassembled L1/L2 capsids [J]. J Virol,1998,72(12):10298-300.
61 Yeager MD, Aste-Amezaga M, Brown DR, et al. Neutralization of human papillomavirus pseudovirions:a novel and efficient approach to detect and characterize HPV neutralizing antibodies [J]. Virology,2000,278(2):570-7.
62 Bousarghin L, Combita-Rojas AL, Touze A, et al. Detection of neutralizing antibodies against human papillomavirus by inhibition of gene transfer mediated by HPV pseudovirions [J]. J Clin Microbiol,2002,40(3):926-32.
63 Unckell F, Streeck RE, Sapp M. Generation and neutralization of pseudovirions of human papillomavirus type 33 [J]. J Vriol,1997,71(4):2934-9.
64 Roden RB, Greenstone HL, Kirnbauer R, et al. In vitro generation and type-specific neutralization of human papillomavirus type 16 virion pseudotype [J]. J Virol,1996, 70(9):5875-83.
65 Rossi JL, Gissmann L, Jansen K, et al. Assembly of human papillomavirus type 16 pseudovirions in Saccharomyces cerevisiae [J]. Hum Gene Ther,2000,11(8):1165-76.
66 Angeletti PC, Kim K, Fernandes FJ, et al. Stable replication of papillomavirus genomes in Saccharomyces cerevisiae [J]. J Virol,2002,76(7):3350-8.
67 Zhao KN, Liu WJ, Frazer IH. Codon usage bias and A+T content variation in human papillomavirus genomes [J]. Virus Research,2003,98:95-104.
68 Zhou J, Liu WJ, Peng SW, et al. Papillomavirus capsid protein expression lever depends on the match between codon usage and tRNA availability [J]. J Virol,1999, 73(6):4972-82.
69 Pyeon D, Lambert PF, Ahlquist P. Production of infectious human papillomavirus independently of viral replication and epithelial cell differentiation [J]. Proc Natl Acad Sci USA,2005,102(26):9311-6.
70 Leder C, Kleinschmidt JA, Wiethe C, et al. Enhancement of capsid gene expression: preparing the human papillomavirus type 16 major structural gene L1 for DNA vaccination purposes [J]. J Virol.2001,75:9201-9.
71 Jacquet A, Magi M, Petry H, et al. High-level expression of recombinant house dust mite allergen Derp 1 in Picha pastoris [J]. Clin Allergy,2002,32:1048-1053.
72 Leder C, Kleinsehmidt J A, Wiethe C, et al. Enhancement of Capsid Gene Expression:Preparing the Human Papillomavirus type 16 Major Structural Gene L1 for DNA Vaccine Purposes [J]. J Virol,2001,75(19):9201-9209.
73李平川,张晓光,周玲,等.按酵母基因优化的HPV6型L1蛋白在大肠杆菌中高效表达[J].病毒学报,2004,20(3)：266-269.
74 Buck CB, Pastrana DV, Lowy DR, et al. Efficient intracellular assembly of papillomaviral vectors [J]. J Virol.2004 Jan;78(2):751-7.
75 Pyeon D, Lambert PF, Ahlquist P. Production of infectious human papillomavirus independently of viral replication and epithelial cell differentiation [J]. Proc Natl Acad Sci U S A.2005 Jun 28; 102(26):9311-6.
76王鹤,于继云,李力.稳定表达人乳头瘤病毒58型E6E7融合基因的B16细胞系的建立[J].中国免疫学杂志.2011,27(12)：1088-1092.
77赵蔚明,于修平,周亚滨.优化密码促进HPV 6b E7蛋白表达及DNA疫苗诱导 的细胞免疫反应[J].中华实验和临床病毒学杂志.2002,16(4)：309-311.
1 Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide [J]. J Pathol,1999,189:12-9.
2 Bosch FX, Lorincz A, Munoz N, et al. The causal relation between human papillomavirus and cervical cancer [J]. J Clin Pathol,2002,55:244-65.
3 Bosch FX, de Sanjose S. The epidemiology of human papillomavirus infection and cervical cancer [J]. Dis Markers,2007,23(4):213-27.
4 Kimbauer R. Booy. F'Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus—like particles that are highly immunogenic [J]. Proc Natl Acad Sci U S A,1992,89(24):12180-4.
5 Hagensee ME, Yaegashi N, Galloway DA. Self-assembly ofhuman papillomavirus type 1 capsids by expression of the LI protein alone or by coexpression of the LI and L2 capsid proteins [J]. J Virol,1993,67(1):315-22.
6 Rose RC, Bonnez w. Reichman RC, et al. Expression of human papillomavirus type 1 1 L1 protein in insect cells:in vivo and in vitro assembly of viruslike particles [J]. J Virol, 1993,67(4):1936-44.
7 Sasagawa T, Pushko P. Steers G, et al. Synthesis and assembly ofvirus-like particles of human papillomaviruses type 6 and type 16 in fission yeast Schizosaccharomyces pombe [J]. Virology,1995,206(1):126-35.
8 Zhou J, Sun XY, Stenzel DJ, et al. Expression of vaecinia recombinant HPV 16 LI and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles [J]. Virology,1991,185(1):251-7.
9 Christensen ND, Kimbauer R, Schiller JT, et al. Human papillomavirus types 6 and 11 have antigenically distinct strongly immunogenic conformationally dependent neutralizing epitopes [J]. Virology,1994.205(1):329-35.
10 Zhou J, Sun XY, Stenzel DJ, et al. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles [J]. Virology,1991,185:251-7.
11 Kirnbauer R, Booy F, Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic [J]. Proc Natl Acad Sci,1992,89:12180-12.
12 Ochi H, Kondo K, Matsumoto K. et al. Neutralizing antibodies against human papillomavirus types 16,18,31.52, and 58 in serum samples from women in Japan with low-grade cervical intraepithelial neoplasia [J]. Clin Vaccine Immunol,2008. 15:1536-1540.
13 Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine [J]. N Engl J Med,2002,347:1645-51.
14 Harro CD, Pang YY, Roden RB, et al. Salty and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine [J]. J Natl Cancer Inst.2001,93(4):284-92.
15 Pastrana DV, Vass WC, Lowy DR, et al. NHPV16 VLP vaccine induces human antibodies that neutralize divergent variants ofHPV16 [J]. Virology,2001,279(1):361-9.
16 Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective [J]. Int J Cancer,2004, 111(2):278-85.
17 Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6,11,16, and 18) L1 virus-like particle vaccine in young women:a randomised doubleblind placebo-controlled multicentre phase II efficacy trial [J]. Lancet Oncol,2005, 6:271-8.
18 The FUTURE II Study Group. Effect of prophylactic human papollomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3 and adenocarcinoma in situ:a combined analysis of four randomized clinical trials [J]. Lancet,2007,369:1861-8.
19 Pomfret TC, Gagnon JM Jr, Gilchrist AT. Quadrivalent human papillomavirus (HPV) vaccine:a review of safety, efficacy, and pharmacoeconomics [J]. J Clin Pharm Ther, 2011,36(1):1-9.
20 Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial [J]. Lancet,2006,367:1247-55.
21 Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years ofa bivalent L1 irus-like particle vaccine against human papillomavirus types 16 and 18: follow—up from a randomised control trial [J]. Lancet,2006,367(9518):1247-55,
22 Johnson KM, Kines RC, Roberts JN, et al. Role of heparan sulfate in attachment to and infection of the murine female genital tract by human papillomavirus [J]. J Virol, 2009,83(5):2067-74.
23 Buck CB, Thompson CD, Roberts JN, et al. Carrageenan is a potent inhibitor of papillomavirus infection [J]. PLoS Pathog,2006,2:69.
24 Rusnati M, Oreste P, Zoppetti G, et al. Biotechnological engineering of heparin/heparan sulphate:a novel area of multi-target drug discovery [J]. Curr Pharm Des,2005,11:2489-99.
25 David Lembo, Manuela Donalisio, Marco Rusnati, et al. Sulfated K5 Escherichia coli Polysaccharide Derivatives as Wide-Range Inhibitors of Genital Types of Human Papillomavirus [J]. Antimicrob Agents Chemother,2008,52(4):1374-81.
26 Donalisio M, Rusnati M, Civra A, et al. Identification of a dendrimeric heparan sulfate-binding peptide that inhibits infectivity of genital types of human papillomaviruses [J]. Antimicrob Agents Chemother,2010,54(10):4290-9.
27 Ross EV, Romero R, Kollias N, et al. Selectivity of protoporphyrin IX fluorescence for condylomata after topical application of 5-aminolevulinic acid:implications for photodynamic treatment [J]. Br J Dermatol,1997,137:736-42.
28 Ayala F, Grimaldi E, Perfetto B, et al. aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism [J]. Photodermatol Photoimmunol Photomed,2008,24(5):237-43.
29 K. Berg, K. Madslien, J.C. Bommer, R. Oftebro, J.W. Winkelman, J. Moan. Light induced relocalization of sulfonated meso-tetraphenylporphines in NHIK 3025 cells and effects of dose fractionation [J]. Photochem. Photobiol.,53 (1991), pp.203-210
30 D. Kessel, M. Conley, M.G. Vicente, J.J. Reiners. Studies on the subcellular localization of the porphycene CPO [J]. Photochem. Photobiol.,81 (2005). pp.569-572
31 D. Kessel. Relocalization of cationic porphyrins during photodynamic therapy.Photochem. Photobiol [J]. Sci.,1 (2002), pp.837-840
32 S. Marchal. A. Francois, D. Dumas, F. Guillemin, L. Bezdetnaya.Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells [J]. Br. J. Cancer,96 (2007), pp.944-951
33 Asta Juzeniene, Petras Juzenas, Johan Moan. Application of 5-Aminolevulinic Acid and Its Derivatives for Photodynamic Therapy In Vitro and In Vivo. In C.J. Gomer, ed. Photodynamic Therapy, Methods in Molecular Biology [J]. Springer Science+Business Media,2010:97-106.
34 Morrow DI, Garland MJ, McCarron PA, et al. Innovative drug delivery strategies for topical photodynamic therapy using porphyrin precursors [J]. J Environ Pathol Toxicol, 2007,26:105-116.
35 Donnelly, McCarron, Morro, et al. Photosensitiser delivery for photodynamic therapy. Part 1:topical carrier platforms [J]. Expert Opin Drug Deliv,2008,5:757-766.
36 Moore RA, Santos EB. Nicholls PK, et al. Intraepithelial DNA immunisation with a plasmid encoding a codon optimised COPV El gene sequence but not the wild type gene sequence completely protects against mucosal challenge with infectious COPV in beagles [J]. Virology,2002,304:451-9
37 Klencke B, Matijevic M, Urban RG, et al. Encapsulated plasmid DNA treatment for human papillomavirus 16-associated anal dysplasia:a phase Ⅰ study of ZYC101 [J]. Clin Cancer Res,2002,8:1028-37.
38 Chien-Fu Hung. Barbara Ma, Archana Monie, et al. Therapeutic human papillomavirus vaccines:current clinical trials and future directions [J]. Expert Opin BiolTher.2008,8(4):421-39.
39 Feltkamp MC, Smits HL, Vierboom MP,et al. Vaccination with cytotoxic T lymphocyte epitope-eontaining peptide protects against a tumor induced by human papillomavirus type 16-transformed cells [J]. Eur J Immunol,1993,23(9):2242-9.
40 teller MA, Gurski KJ, Murakami M, et al. Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirustype 16 E7 [J]. ClinCancerRes,1998,4(9):2103-9.
41 Muderspach L, Wilczynski S, Roman L. et al. A phase Ⅰ trial of a human papillomavirus(HPV) pepfide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV16 positive [J]. ClinCancerRes,2000,6(9):3406-16.
42 Hiranuma K, Tamaki S, Nishimura Y, et al. Helper T cell determinant peptide contributes to induction ofcellular immune responses by peptide vaccines against hepatitis C virus [J]. J Gen Virol,1999,80(Pt 1):187-93.
43 Bristol JA, Orsini C, Lindinger P, et al. Identification of a ras oncogene peptide that contains both CIM(+)and CD8(+)T cell epitopes in a nested configuration and elicits both T cell subset responses by peptide or DNAimmunization [J]. Cell Immunol,2000, 205(2):73-83.
44 Zwaveling S, Ferreira Mota SC, Nouta J, et al. Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides [J]. J Immunol,2002,169(1):350-8.
45 Thompson HS, Davies ML, WaRs MJ, et al. Enhanced immunogenicity of a recombinant genital warts vaccine adjuvanted with monophosphoryl lipid A [J]. Vaccine, 1998,16(20):1993-9.
46 Daflarian P, Mansour M, Benoit AC, et al. Eradication of established HPV 16 expressing tumors by a single administration of a vaccine composed of a liposome—encapsulated CTL-T helper fusion peptide in a water-in oil emulsion [J]. Vaccine,2006.
47 Boursnell ME, Rutherford E. Hiekling JK, et al. Construction and characterisation of a recombinant vaccinia virus expressing human papillomavirus proteins for immunotherapy of cervical cancer [J]. Vaccine.1996,14(16):1485-94.
48 Brandsma, Shlyankevich M, Zhang L, et al. Vaccination of rabbits with an adenovirus vector expressing the papillomavirus E2 protein leads to clearance of papillomas and infection [J]. J Virol,2004,78(1):116-23.
49 Garcia-Hemandez E, Gonzalez-Sanchez JL, Andrade-Manzano A, et al. Regression of papilloma hig}1-grade lesions(CIN 2 and CIN 3)is stimulated by therapeutic vaccination with MVA E2 recombinant vaccine [J]. Cancer Gene Ther,2006.
50 Reyes-Gutierrez P, Alvarez-Salas LM. Cleavage of HPV-16 E6/E7 mRNA mediated by modified 10-23 deoxyribozymes [J]. Oligonucleotides,2009.19(3):233-42.
51 W Gul, E Paynel, S Sun, et al. Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs [J]. Cancer Gene Therapy,2010,1-9.
52 Dymalla S, Scheffner M, Weber E, et al. A novel peptide motif binding to and blocking the intracellular activity of the human papillomavirus E6 oncoprotein [J]. J Mol Med,2009,87(3):321-31.
53 Wierzbicka M, Jackowska J, Bartochowska A, et al. Effectiveness of cidofovir intralesional treatment in recurrent respiratory papillomatosis [J]. Eur Arch Otorhinolaryngol,2011 Apr 26. [Epub ahead of print]
54 Donne AJ, Hampson L, He XT, et al. Cidofovir induces an increase in levels of low-risk and high-risk HPV E6 [J]. Head Neck,2009,31:893-901.
55 G.P Talwar, Sajad A Dar, Mahendra K Rai, et al. A novel polyherbal microbicide with inhibitory effect on bacterial, fungal and viral genital pathogens [J]. International Journal of Antimicrobial Agents,2008,32:180-185.