前列腺特异性启动子在慢病毒介导基因治疗中的研究进展

前列腺癌多发生于老年男性,其发病率和死亡率正在逐年上升。对于早期前列腺癌,采用阻断雄激素的去势治疗可以有效抑制肿瘤生长,但在治疗2～3年后大部分进展为去势抵抗性前列腺癌,这是导致患者死亡的主要原因。目前,对晚期尤其是去势抵抗性前列腺癌尚缺乏有效的治疗策略,随着生物技术的兴起与发展,针对恶性肿瘤的生物靶向治疗研究日趋深入和成熟,其中慢病毒介导的基因治疗成为研究的热点。运用特异性启动子调控相关基因的表达,可以进一步提高抗肿瘤的靶向性和安全性。本文就目前在基础研究中,前列腺特异性启动子在慢病毒介导下基因靶向治疗前列腺癌的研究现状进行综述。     

肺腺癌组织特异性自杀基因治疗实验研究

目的 探讨肺腺癌组织特异性自杀基因治疗的安全性及有效性。方法 采用病毒感染法，将癌胚抗原(CEA)基因启动子所驱动的CD基因的组织特异性逆转录病毒载体(G1CEACDNa)，导入分泌CEA的肺腺癌细胞系A549细胞．研究裸鼠体内抑瘤效果；应用重组逆转录病毒裸鼠体内治疗A549肿瘤，观察G1CEACDNa／5-氟胞嘧啶(5-FC)对A549细胞致瘤裸鼠的治疗作用及毒副反应。结果 (1)将转基因的A549细胞和未转基因的A549细胞接种至裸鼠皮下．两者成瘤性无明显差异；(2)在转基因细胞致瘤裸鼠实验中，5-FC对转CEA启动子调控自杀基因的肿瘤生长具有明显的抑制作用；(3)将G1CEACDNa重组逆转录病毒上清直接注射到裸鼠成瘤部位．然后腹腔内注射5-FC同样获得明显的抑瘤效果；(4)与直接注射5-FU相比，组织特异性自杀基因治疗对骨髓的抑制明显降低。结论 组织特异性自杀基因治疗可能成为肿瘤治疗个体化的重要方法之一。     

肝癌自杀基因治疗研究进展

自杀基因治疗民为肝癌基因治疗研究的热点。本文对近年来有关进展,如自杀基因的毒性作用、影响因素、载体、靶向性及与其它方法的联合应用作一综述。     

自杀基因治疗恶性肿瘤研究进展

恶性肿瘤的基因治疗是现代医学领域的研究热点，其中自杀基因疗法可能成为一种极具潜力和临床应用价值的治疗手段，在治疗范围上，已扩大到全身所有脏器及各种组织类型的恶性肿瘤，在提高其转录靶向调控机制上，已发现了许多特异性启动子元件，来增强自杀基因作用的特异性及可调控性，并已尝试利用辐射诱导来提高其转基因表达的外源性调控机制；此外，采用自杀基因与集落刺激因子(GM—CSF)、细胞因子等联合应用，诱导产生更强的抗肿瘤免疫，进一步增强杀伤肿瘤的效力。     

自杀基因治疗肿瘤研究进展

基因治疗的策略主要有:(１)基因替换和基因补充,转换突变的癌基因或补充肿瘤细胞中缺失的抑癌基因;(２)基因导入以增强免疫效应细胞的抗癌效能。如:导入细胞因子基因和(或)免疫共刺激分子基因以增强免疫效应细胞的杀癌能力;(３)基因导入以增强肿瘤细胞的免疫原性,如:导入ＭＨＣＩ类抗原基因;(４)肿瘤药物敏感基因治疗——自杀基     

乳腺癌的自杀基因治疗研究进展

从自杀基因治疗乳腺癌的研究现状、自杀基因体系、旁观者效应、临床试验研究等方面综述了近几年自杀基因治疗乳腺癌的实验和临床研究的进展     

乳腺癌的自杀基因治疗研究进展

从自杀基因治疗乳腺癌的研究现状、自杀基因体系、旁观者效应、临床试验研究等方面综述了近几年自杀基因治疗乳腺癌的实验和临床研究的进展。     

组织特异性启动子及其在肿瘤基因治疗中的应用

随着基因治疗研究的深入，愈来愈多的组织特异性启动子已被用于调控目的基因在靶器官中的表达，尤其是携带治疗性基因可以实现对肿瘤组织的特异性杀伤作用，组织特异性启动子的应用已成为基因治疗中的一个重要手段，现综述各系统启动子的分类及其应用。     

恶性肿瘤自杀基因治疗研究进展

经过数年的发展,目前国际上已有二百多个基因治疗项目应用于临床,其中恶性肿瘤的基因治疗占了２／３,而恶性肿瘤的自杀基因治疗又占恶性肿瘤基因治疗的五分之一以上。恶性肿瘤的自杀基因治疗已由最早的治疗卵巢癌（１９９１年）,发展到多种肿瘤和疾病的治疗,如：脑瘤、恶性黑色素瘤、头颈部鳞癌、前列腺癌、多发性骨髓瘤、间皮瘤、柔脑膜瘤、中枢神经系统疾病及骨髓移植等各个方面［１］。所谓自杀基因（ｓｕｉｃｉｄｅｇｅｎｅ）是指在一定条件下,可以引起细胞自动死亡的基因。它有两类：一是基因表达产物本身对细胞有毒性作用,如白…     

自杀基因治疗乳腺癌的研究进展

自杀基因疗法是近年乳腺癌基因治疗研究的热点之一。这类基因所编码的酶能将无细胞毒性或低细胞毒性的前体药转化成细胞毒性代谢产物，经靶向性转导或靶向性转录，选择性地杀伤肿瘤细胞。简要介绍该疗法的机理以及基因治疗载体、靶向性治疗和联合基因治疗的新进展。     

卵巢癌的自杀基因治疗

卵巢癌自杀基因治疗多采用HSVtkGCV系统和CD5FC系统。通过自杀基因的表达产物将无毒性的药物转化为有毒性的药物及旁观者效应杀死肿瘤细胞。尽管目前还存在转染效率、靶向性等问题有待改进，但随着自杀基因的不断完善，联合基因、联合细胞因子治疗及联合放疗等策略的采用，自杀基因在卵巢癌治疗上将具有广阔的应用前景。     

Strategies for Prostate Cancer Gene Therapy

Gene therapy for prostate cancer is a relatively new experimental treatment modality and several different therapeutic approaches are being considered. Prostate cancer is the most commonly diagnosed cancer in males and has unique features that make it ideal for gene therapy. Although prostate cancer that is confined to the gland can be cured in many of the patients using local treatments (radical prostatectomy or irradiation therapy), the long-term failure rate of these therapies suggests that cancers can metastasize relatively early in the course of the disease. Once prostate cancer has metastasized there are no curative therapies. The greatest challenge in the treatment of advanced prostate cancer is to access and eliminate metastatic cells. Therefore, successful prostate cancer gene therapy will ultimately require an effective strategy to kill cancer cells both at the site of the primary tumor and at distant metastatic sites. In this article we review many aspects of gene therapy specifically relevant for prostate cancer. We discuss the unique advantages and disadvantages of nonviral and viral gene delivery systems. Evidence that gene delivery directly into tumors, in situ, is effective for prostate cancer is presented. We provide a broad review of three general approaches or strategies for prostate cancer gene therapy: corrective, cytoreductive, and immuno-modulatory gene therapy. Replacement of the tumor suppressor gene p53 is the best studied example of corrective gene therapy. The cytoreductive gene therapy that has been used most extensively is herpes simplex virus thymidine kinase (HSV-tk) combined with the prodrug ganciclovir. Immunomodulatory gene therapy approaches such as enhancement of cancer cell recognition, e.g. with antigen encoded gene vaccine approaches, and augmentation of the cellular immune response with specific immunomodulatory molecules such as interleukin-12 have the potential to effectively treat both local prostate cancer and distant metastases.     

基因治疗在前列腺癌中的应用

目前晚期前列腺癌局部和全身治疗手段都存在一定局限性，为此人们开始寻找其他方法，基因治疗的出现给晚期前列腺癌治疗带来新的希望，全文就当今前列腺癌基因治疗的情况进行了学习和总结。     

自杀基因治疗乳腺癌的研究进展

自杀基因疗法是近年乳腺癌基因治疗研究的热点之一。这类基因所编码的酶能将无细胞毒性或低细胞毒性的前体药转化成细胞毒性代谢产物 ,经靶向性转导或靶向性转录 ,选择性地杀伤肿瘤细胞。简要介绍该疗法的机理以及基因治疗载体、靶向性治疗和联合基因治疗的新进展     

肿瘤自杀基因靶向治疗的研究进展

自杀基因治疗是目前肿瘤基因治疗中的研究热点.本文重点从自杀基因的种类、载体、作用机制和发展应用前景等几方面进行综述.其中HSV1-tk/GCV自杀基因系统是研究最多、临床价值最为明确的自杀基因系统之一.治疗机制上除通过直接作用和旁观者效应发挥作用外,还从自杀基因联合使用、趋化因子等细胞因子作用、自杀基因与放射治疗联合作用、自杀基因与免疫治疗联合使用等多方面进行了探索和研究.众多研究结果认为自杀基因治疗是一种具有良好应用前景的肿瘤治疗方法,但在临床应用上还有很多问题需要解决,如将自杀基因安全、高效地转染到人体肿瘤组织和细胞中的方法,如何能使自杀基因在靶组织中稳定表达并发挥作用,各种治疗方法的协同作用等,均有待于我们在今后的研究中进一步解决.     

卵巢上皮癌自杀基因疗法研究进展

近年来卵巢上皮癌的自杀基因疗法取得很大进展,主要体现在:由组织特异性启动子参与调控,增强基因转染的靶向性,降低对非肿瘤组织的副作用;自杀基因(如HSV-TK基因)与免疫增强基因的联合应用;自杀基因与放射治疗的联合应用;增强自杀基因表达效率的辅助方法.     

Suggesting Tissue-Specific MSMB Gene Promoter as a Novel Approach for Prostate Targeted Gene Therapy

Background and aim: Prostate cancer is the second most common cancer among men that has affected their quality of life. This study aimed to find prostate tissue-specific genes using bioinformatics methods to specifically target prostate cells in case of metastasis to other tissues. Materials and Methods: In this study, after finding a specific gene (MSMB)  that is highly expressed in cancer, the optimal promoter region of this gene was isolated and inserted in an expression vector. Then, this vector was transfected into two prostate cancer cell lines (DU145 and LNCaP) and three non-prostate cell lines  (LX-2, MRC-5, and U87) using the PEI chemical method. The expression of this vector in these cells was examined using fluorescent microscopy and flow cytometry. Results: We observed that the expression of MSMB promoter in DU145 cell line has a much higher activity than the CMV promoter, which is a ubiquitous promoter. The MSMB promoter didn’t show any activity in cells other than that of prostate derived cell lines. Conclusion: MSMB  gene promoter with specific expression and high efficiency in prostate tissue compared to CMV promoter can play an essential role in gene therapy of prostate cancer.     

自杀基因疗法联合化疗对癌胚抗原表达型肺肿瘤的杀伤作用

目的：探讨阳离子脂质体介导E.coli cd/HSV-1tk融合自杀基因联合长春瑞滨对癌胚抗原阳性肺癌的体内杀伤作用。方法：裸鼠皮下接种肺癌细胞SPCA－1后第5、9、13天,腹腔注射阳离子脂质体／pE-CEAcd-tk复合物,于第6－15天连续腹腔注射5－氟胞嘧碇＋丙氧鸟苷前体药物进行自杀基因治疗。于第5、13天给予长春瑞滨进行联合治疗。结果：阳离子脂质体介导融合自杀基因联合长春瑞滨使小鼠皮下的肿瘤结节的生长受到显著抑制,其平均瘤体体积显著小于单独自杀基因或化疗治疗组的平均瘤体体积（P＜0．01）。结论：阳离子脂质体介导E.coli cd/HSV-1tk融合基因联合长春瑞滨化疗在体内在有效抑制肺瘤的生长,为癌胚抗原阳性肺癌的治疗提供了1条新的途径。     

In situ Gene Transfer and Suicide Gene Therapy of Gastric Cancer Induced by N-Ethyl-N'-nitro-N-nitrosoguanidine in Dogs

Gene therapy could potentially revolutionize the treatment of gastrointestinal (GI) tract cancer. The aim of this study was to establish a practical method of gene transfer which would be applicable to human gastric cancer. Retrovirus or/and adenovirus vectors carrying the lacZ marker gene were transferred in situ by needle through an endoscopic biopsy channel into primary gastric cancer in six male beagle dogs that had been treated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). In addition, an adenovirus vector carrying the herpes simplex virus thymidine kinase (Ad.CAGHSV-TK) gene was introduced in situ into cancer tissues in the stomach of three dog, and the animals were treated with intravenous ganciclovir (GCV). Retrovirus-producing cells which expressed the lacZ gene were specifically localized to the injection site in the stomach. The lacZ gene was more widely transferred into the tumor by the adenovirus vector than by retrovirus-producing cells. Improvement of the needle used for gene transfer and the use of multiple injections per tumor led to more diffuse transfer of the vector into the tumor. The Ad.CAG lacZ gene was also transferred into regional lymph nodes of the stomach. Moderate to diffuse degeneration of the primary cancer tissues of the stomach was found after Ad.CAGHSV-TK/GCV gene therapy. Moreover, almost complete tissue degeneration was observed in the regional lymph nodes of the stomach. An adverse effect of HSV-TK/GCV gene therapy was acute hepatotoxicity, which was not found after Ad.CAG lacZ gene transfer, but was found after high-titer Ad.CAGHSV-TK gene transfer followed by GCV. These findings suggest that in situ gene transfer of a suicide gene followed by prodrug treatment may be applicable not only to primary tumors, but also to lymph node metastases of gastric cancer, though further study of both beneficial and adverse effects is required before clinical usage.