| Background:Condyloma acuminata（CA）,a common sexually transmitted disease（STD）,which is caused by human papillomavirus（HPV）and is a benign hyperplasia disease mainly in the genital and perianal.It also known as venereal warts,anogenital warts or genital warts.At the beginning,condyloma acuminata is the small and soft verrucous pink papules,and then they become bigger,numerous and uneven as the time goes.It has no obvious symptoms at the beginning.It can be divided into five types according to the shape of warts;including popular type,papillary type,cauliflower type,comb type and mushroom-like type.The lesions could manifest as rough,gray or pink in the surface.Meanwhile,it becomes ulceration,oozing,bleeding or infection result from friction or maceration associate with itching,pressure feeling,and pain.In the past fifteen years,the incidence of condylomata acuminata is increasing five times than before in the USA,become one of the most prevail STD in the Europe and America,also in china.Approximately twenty percents patients account for the total patients with venereal disease in some areas in china.It is more common in southern than in northern in China.Age range from 16 to 35 years is the mainly population in this disease with highly contagious and lower incidence than the non-gonococcal urethritis and gonorrhea in the foreign countries.The diagnosis of CA is accord to the clinical symptoms and together with histopathological examination if necessary.However,it is difficult to diagnose sub-clinical infection and latent infection.Some studies found that the urethroscopy fluoroscopy proved to be a promising discovery of the early period of the urethral condyloma,which can also used to detect the photosensitization in clinical and sub-clinical HPV infection.In recent years,some studys on 5-aminolevulinic acid-photodynamic diagnose（ALA-photodynamic diagnosis,ALA-PDD）found that it is useful for the diagnosis of CA,which can detect all types of lesions,including clinical,sub-clinical and latent infection,without traumatic,has a great significance for the subsequent photodynamic therapy（photodynamic therapy,PDT）and completely curing CA and reducing the relapse rate.In the present,the treatment of CA including physical therapy,for instance,microwave therapy、cryotherapy、etincelage、carbon dioxide laser etc;topical medicine treatment,for example,podophyllotoxin cream and imiquimod cream etc.and systemic immune regulation therapy.No matter whatever treatment mentioned above,the relapse rate of CA is very high and it prone to cause scaring and the disfiguring of the genital area.The persistent and recurrent infection of HPV have the risk to cause cancer,so it of great importance to eradicate the HPV infection of genital areas.Photodynamic therapy（Photodynamic therapy,PDT）is a new treatment in recent years,the mechanism is the locally application of photosensitizers in certain time to gain high concentration on target tissues,and then use the appropriate wavelength of light irradiation it.Through a series of photochemical reactions in the target tissue,a large number of singlet oxygen and the release of fluorescence,singlet oxygen cytotoxicity result in the death of the target tissue.Tappeiner point out that photodynamic therapy must need the participation of the molecular oxygen.After the initial sensitization process,photosensitizers absorb photons from the ground state to a very unstable singlet excited state of the photosensitizer which is activated to return to the ground state emits fluorescence（the fluorescence is used in the PDD）,but the activation of photosensitivemolecules must through intersystem crossing（Intersystelncrossing,ISC）and changes in electron spin to form a more stable activation of the triplet state（triplet）,which issued by the phosphorescence（wavelength than the fluorescence to long）back to the ground state.Application of energy conversion in the process of fluorescence and photodynamic diagnosis was subsequently more and more used in the diagnosis and treatment of a variety of tumors.With the development of second-generation photosensitizer benzoporphyrin such as 5-ALA at the lately 1980s which has a photosensitive activity and widely absorption spectra and tissue selectivity than the first generation that make it has been widely applied in clinical practice,in particular,is a major breakthrough in the diagnosis and treatment of tumors.The Canadian scholars such as Kennedy etc.used ALA-PDT for the local skin basal cell carcinoma,Bowen disease,squamous cell carcinoma and get a satisfactory efficacy.From then on,ALA-PDT began used widely in the dermatology therapeutic.In the field of dermatology,5-aminolevulinic acid（ALA）as a photosencitizer which mediated photodynamic therapy,was authorized by US food and drug administration（FDA）in the treatment of actinic keratoma in 1999.ALA（the second generation photosencitizer）is the endogenous substance of biosome and precursor of the heme in vivo,which can be used as a photosencitizer to treat all kinds of cancers.Under normal circumstance,the amount of ALA in cells is very little,ALA itself can not generate photosensitivity.After exogenous ALA enter into the body,it can be absorbed and accumulated preferentially by the highly hyperplastic cells（such as HPV infected cells）.In cells ALA is turned into protoporphyrin Ⅸ（PpⅨ）,which is a potent photosencitizer.After the irradiation of specific wavelength of light,PpⅨcan be excited to perform the visible brick-red or red fluorescent.Wang et al.applied photodynamic diagnosis（PDD）in 30 patients with condylomata acuminata,all warty lesions and subclinical lesions（n=25）showed red fluorescence and harbored HPV DNA（HPV6 or 11）.Latent HPV infections at 0.5-2 cm away from the warty lesion in 18 patients also showed red fluorescence.It suggest that the feasibility and accuracy for ALA-PDD to diagnose subclinical infection and latent infection.In the resent years,the application of PDT has made a significant effect,especially in the treatment of urethral and cervical condyloma acuminata.This method significantly improved the present treatment of condylomata acuminate.Stefanaki et al.studied 12 male patients with condylomata acuminata,whose confirmation of diagnosis was established with conventional histology and polymerase chain reaction.Lesions were treated with 20%ALA and the irradiation of mean 650nm wavelength of light with a dose of 70J/cm2 or 100J/cm2 were given.The overall cure rate was 72.9%,12 months after treatment.Wang et al.first described the study of ALA-PDT on the treatment of condylomata acuminata,164 patients with urethral condylomata acuminata were treated with 10%ALA and irradiated by He-Ne laser light of 632.8nm,with a dose of 100J/cm2.The average interval time was 3h,one treatment per week,the maximum number of treatment was four.The overall recurrence rate was only 5%,6-24 months after treatment.The treatment was well tolerated in patients.Liu et al.applied ALA-PDT on the treatment of cervical condylomata acuminate,3 months after treatment,the total complete remission was 100%and the total recurrence rate was 5%;the side effect of PDT including mild burning and tingling feeling of illuminating areas.Compared to the traditional therapy,topical ALA-PDT is a safety、effective、well-tolerated and lower recurrent treatment for cervical CA.Although PDT has made significant progress in the treatment of condylomata acuminate.The studies on the mechanism of ALA-PDT in the treatment of genital warts at home and abroad are very few,it still requires further study.The main mechanism of photodynamic therapy is to induce apoptosis of infection cells.Numerous of studies on apoptotic pathway or called programmed cell death is a ATP-dependent process which is a cell follow their own procedures to the end of its life under certain physiological or pathological conditions with strict genetic control and selectivity.Apoptosis is widespread exist in humans and a variety of plants and animals,which is an indispensable part of the structure of the tissue throughout all biological life activities.The abnormal regulation of apoptosis can disrupt the balance between cell proliferation and cell death,causing a range of diseases including cancer.Bax and bcl-2 have played an important role in the regulation mechanism of apoptosis and have been studied deeply,bax promote apoptosis while bcl-2 inhibit apoptosis.Bax、bcl-2 are important regulation factors of intrinsic apoptotic pathway（also called mitochondrial pathway）.The photosensitizer located in mitochondrial（such as ALA）can cause rapid and light-dependent damage to the mitochondrial gatekeeper proteins,such as anti apoptosis proteins bcl-2 and bcl-xL.Subsequently the caspase activation molecule such as cytochrome C of mitochondrial release into the cytoplasm.Fas is apoptosis receptor of cells surface,after combining with fas ligand,can tigger extrinsic apoptosis.This study is the first time to detect the level of bax、bcl-2 and fas mRNA and bax、bcl-2 proteins in CA lesions before and after the treatment of ALA-PDT,from gene and protein aspects to explore the mechanism of ALA-PDT in the treatment of CA.Objectives:By detecting the expression of the apoptosis related factors（Bax,Bcl-2,Fas）and apoptosis related protein（Bax、Bcl-2）in those patients with condylomata acuminata before and after the treatment with ALA-photodynamic therapy（ALA-PDT）,to explore the mechanism of ALA-PDT in the treatment of condylomata acuminata.Methods:1.A total of 35 patients diagnosed with condylomata acuminata were enrolled in this study and were treated by ALA-PDT.To collect the lesions of condylomata acuminata before and after the treatment and to measure the expression of Bax,Bcl-2 and Fas mRNA with Fluorescence quantitative reverse transcription polymerase chain reaction.2.A total of 35 patients diagnosed with condyloma acuminata were enrolled in this study and were treated by ALA-PDT.To collect the lesions of condylomata acuminata before and after the treatment and to measure the expression of Bax and Bcl-2 proteins with immunohistochemical staining.Results:1.The Bax、Bcl-2 and Fas gene fragments have been detected in these subjects.Compared with before treatment with ALA-PDT,after the treatment with ALA-PDT,the expression of Bcl-2 mRNA were significantly decreased,whereas the Fas mRNA expression were significantly increased,Bax mRNA expression levels were mildly elevated,but there were no statistical significant.2.The Bax and Bcl-2 proteins have been detected in these subjects.Compared with before treatment with ALA-PDT,after the treatment with ALA-PDT,the expression of Bcl-2 protein were significantly decreased,Bax protein expression levels were mildly elevated,but there were no statistical significant.Conclusion:ALA-PDT is an effective treatment for condylomata acuminata,especially for urethral and cervical condylomata acuminata.It can maintain the morphology of genital areas,reduce the recurrent rate of CA and well-tolerated by patients.It can promote cells apoptosis in condylomata acuminata by inducing cell surface apoptosis receptor Fas expression and inhibiting apoptosis inhibitory factor Bcl-2 expression.The specific apoptosis pathways include mitochondrion-mediated apoptosis（intrinsic pathway）and death receptor-mediated apoptosis（extrinsic pathway）. |
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