胃肠道肿瘤基因治疗策略

肿瘤的基因治疗就是应用基因工程的方法,校正或修复与肿瘤发生相关的变异基因,或改变某些细胞的生物学特性,通过直接细胞杀伤作用、免疫调节或纠正遗传错误等逆转肿瘤的恶性状态,从而达到治疗肿瘤目的的一种方法。目前国内外学者将这种新型治疗手段应用于胃肠道肿瘤治疗领域,有些已经试用于临床治疗,并取得了较好的疗效。１　免疫基因治疗近年所开展的基因治疗中,以免疫基因治疗的研究最为多见,而细胞因子基因治疗又是免疫基因治疗的热点。１９９０年,Ｂｌａｎｋｅｎｓｔｅｉｎ首先提出肿瘤靶向的细胞因子基因治疗（ｔｕｍｏｒｃｅ…     

肿瘤基因治疗的研究现状和展望

基因治疗(gene therapy)是随着DNA重组技术、基因克隆技术等的成熟而发展起来的最具革命性的医疗技术之一,它是以改变人的遗传物质为基础的生物医学治疗手段。经过近三十年的发展,基因治疗已经由最初用于单基因遗传病的治疗扩大到恶性肿瘤、感染性疾病、心血管疾病、自身免疫性疾病、代谢性疾病等多种重大疾病的治疗,其中针对恶性肿瘤的基因治疗临床试验方案占了总数的2/3。本文将主要聚焦全球基因治疗的发展历史和我国肿瘤基因治疗的发展现状,重点介绍肿瘤基因治疗所用的表达载体、基因导入系统、临床试验、重点产品的研发和产业化发展以及近年来基因治疗在恶性肿瘤、重大遗传性疾病等治疗领域所取得的重点突破。此外,还从基因的体内递送、基因治疗的安全性、新技术用于肿瘤的基因治疗、肿瘤基因治疗与其他治疗方法的联合应用、基因检测技术与基因治疗相结合等五个方面,对未来肿瘤基因治疗所面临的发展机遇和挑战进行重点阐述。有理由相信,随着肿瘤基因治疗关键技术的不断突破,未来几年将是肿瘤基因治疗产品上市的重要时期,将为恶性肿瘤的临床治疗提供更多的新选择。     

肿瘤基因治疗研究的现状和展望

肿瘤基因治疗取得了飞速发展，我国在肿瘤的基因治疗方面已开展了上当广泛的研究并取得了一定的进展，但在研究的规模和水平上与国外相比仍有差距。把握住肿瘤基因治疗研究的发展方向如获取治疗效果显著的抗肿瘤目的的基因、构建肿瘤细胞特异性表达载体、实现肿瘤靶向性的基因转染并使具体治疗方式简便实用化且清醒地去对待和研究将会有益于肿瘤基因治疗研究的发展。     

恶性肿瘤基因治疗的研究进展

由于分子生物学技术的高速发展,基因治疗技术发展的速度比任何领域都快,尤其是肿瘤基因治疗进展更为迅速,走在了基因治疗的前列。在国际批准的100余个基因治疗方案中,肿瘤基因治疗就有70个左右,建     

肿瘤基因治疗的研究进展

肿瘤是当今社会影响人类健康的主要疾病之一,近年来,随着人们对肿瘤免疫、肿瘤病因及分子机制等研究的深入,肿瘤基因治疗获得突飞猛进的发展,并逐渐走向成熟,批准进入临床试验的基因治疗药物逐年增多。肿瘤基因治疗原理是将目的基因用基因转移技术导入靶细胞,使其获得特定的功能,继而执行或介导对肿瘤的杀伤和抑制作用,或保护正常细胞免受化学治疗与放射治疗的严重伤害。针对各种肿瘤发生、发展机制,肿瘤基因治疗大致从以下几个方面着手,包括抑制癌基因的表达活性、补偿肿瘤抑制基因的活性、抑制血管生成、免疫基因治疗、自杀基因疗法和肿瘤…     

恶性肿瘤基因治疗与放射治疗

恶性肿瘤的发生是细胞内原癌基因活化和抑癌基因的异常表达,即“基因病变”（ｇｅｎｅｔｉｃｅｓｉｏｎｓ）所致,当这种“病变”积累到一定程度,正常的体细胞即可突变为肿瘤细胞。肿瘤的基因治疗正是依此研究结果而设计的一种治疗方案,即将外源性ＤＮＡ片段稳定地插入到靶细胞基因组中,使其在肿瘤部位表达高浓度的产物或在体外相关细胞内重组后再导入体细胞中表达,从而抑制肿瘤恶性表型,控制肿瘤细胞生长和繁殖。现就目前肿瘤基因治疗的策略、实施方案及其与放射治疗的结合方式综述如下。１　肿瘤基因治疗策略　　肿瘤基因治疗主要集…     

目的基因的研究进展

目的基因的研究进展王伟（综述）姚松朝（审校）基因技术及基因治疗已广泛地用于医学各个领域，而肿瘤基因治疗技术已随着肿瘤免疫学、肿瘤分子生物学的发展而发展。本文对作为肿瘤基因治疗为主要环节的目的基因的若干进展作一概述。１目的基因的概念基因治疗就是以外源正...     

卵巢癌基因治疗研究现状及进展

随着肿瘤基因治疗研究的迅速发展,卵巢癌的基因治疗也成为近年来研究热点.载体是基因转导和表达的关键.基因治疗方案包括分子化学治疗、突变补偿、提高潜在免疫力和肿瘤耐药基因治疗等.联合基因治疗弥补了单基因应用的不足,可显著提高基因治疗的疗效.     

肿瘤基因治疗的研究进展

目的:综述分析国内外肿瘤基因治疗研究现状的文献,为基础与临床研究提供研究方向、思路和资料。方法:应用MEDLINE、CA、CBMdisc、CMCC、CJFD和CSTPCD等数据检索系统及数据库,以"肿瘤基因治疗"等为关键词,检索1998-01～2007-06与肿瘤基因治疗相关的文献。纳入标准:1)肿瘤基因治疗的动物及临床试验研究,包括方法、效果及进展;2)肿瘤基因治疗与其他生物疗法疗效、不良反应及优缺点的比较。根据纳入标准,粗选143篇文献,最后17篇文献纳入综述分析。结果:基因治疗作为肿瘤治疗的新手段是随着DNA重组技术的成熟而发展起来的,是以改变遗传物质为基础的生物医疗技术,它通过将正常基因或有治疗作用的基因导入靶细胞来纠正突变或有缺陷的基因,以达治疗目的。基因沉默疗法、自杀基因疗法、免疫基因疗法、基因替代疗法、反义基因疗法、多药耐药相关基因治疗、抗肿瘤新生血管治疗和抗端粒酶治疗等均取得显著进展。结论:不同的肿瘤基因治疗方法各有利弊,随着治疗方法与病毒载体的不断改造和完善,基因的转移率、靶向性与安全性不断提高。     

p53基因治疗恶性肿瘤的研究进展

p53基因是一种十分重要的抑癌基因，在机体组织细胞的生长、发育、分化等过程中起重要作用。p53基因丢失、缺失或突变可以导致人类恶性肿瘤的发生，而且与肿瘤的分化程度相关。目前，以p53基因治疗肿瘤的研究发展非常迅速。利用p53基因治疗肿瘤已成为继手术、放疗、化疗后的又一种有希望的肿瘤生物治疗方法。最近，有学者引入介入技术经肿瘤供血动脉直接灌注重组p53，为p53基因治疗肿瘤开辟了一条新途径。本文就p53基因的结构、功能与肿瘤的关系以及在肿瘤基因治疗中的应用综述如下。     

Cancer gene therapy targeting cellular apoptosis machinery

The unraveling of cellular apoptosis machinery provides novel targets for cancer treatment, and gene therapy targeting this suicidal system has been corroborated to cause inflammation-free autonomous elimination of neoplastic cells. The apoptotic machinery can be targeted by introduction of a gene encoding an inducer, mediator or executioner of apoptotic cell death or by inhibition of anti-apoptotic gene expression. Strategies targeting cancer cells, which are achieved by selective gene delivery, specific gene expression or secretion of target proteins via genetic modification of autologous cells, dictate the outcome of apoptosis-based cancer gene therapy. Despite so far limited clinical success, gene therapy targeting the apoptotic machinery has great potential to benefit patients with threatening malignancies provided the availability of efficient and specific gene delivery and administration systems.     

前列腺癌的基因治疗

面对治疗前列腺癌有限的几种治疗模式,其有限的成功率势必需要一种更加有效的治疗方案作为替代或补充,随着生物科技的迅速发展,前列腺癌基因治疗的研究也在不断的深入,基于前列腺癌的分子表达,通过基因介导以达到治疗的目的,在研究过程当中多种基因治疗方案已经取得了很大的发展,这些方法主要有以下几类:免疫基因治疗;细胞减数基因治疗;条件复制型腺病毒.我们相信这些新的治疗方案在不久的将来定将给患者带来巨大的福音,现对这一方法进行综述.     

前列腺癌的基因治疗

面对治疗前列腺癌有限的几种治疗模式,其有限的成功率势必需要一种更加有效的治疗方案作为替代或补充,随着生物科技的迅速发展,前列腺癌基因治疗的研究也在不断的深入,基于前列腺癌的分子表达,通过基因介导以达到治疗的目的,在研究过程当中多种基因治疗方案已经取得了很大的发展,这些方法主要有以下几类：免疫基因治疗;细胞减数基因治疗;条件复制型腺病毒。我们相信这些新的治疗方案在不久的将来定将给患者带来巨大的福音,现对这一方法进行综述。     

基于非病毒基因载体的肿瘤免疫联合治疗研究进展

据全球癌症数据统计,2020年新发癌症病例1 929万例,我国肿瘤发病率占全世界23.7%,寻找治疗肿瘤有效手段迫在眉睫,而基于基因的免疫治疗在癌症方面具有巨大潜力。本文总结近年来基于纳米递送系统的基因免疫治疗在癌症免疫及免疫联合治疗中应用的种类及发展情况,这其中包括mRNA、DNA和基因编辑疗法等。通过该综述研究,有望对基于非病毒基因载体的肿瘤免疫联合治疗领域有更深刻的了解,为临床前基础研究提供依据。     

表达小干扰RNA的条件增殖腺病毒与肿瘤

RNA干扰(RNAi)是一种由双链RNA介导的基因沉默现象。RNAi作为强有力的研究工具正在基因功能组学领域掀起一场真正的革命,也成为当今肿瘤基因治疗研究的热点。条件增殖腺病毒(CRAd)是一类仅在肿瘤细胞内特异增殖新型腺病毒载体,通过CRAd介导的小干扰RNA(siRNA)可以靶向肿瘤细胞,且随着病毒增殖反复表达siRNA,进一步加强siRNA介导的癌基因沉默效果。因此, siRNA-CRAd模式开辟了肿瘤基因治疗的新途径。     

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.     

The adeno-associated virus-mediated HSV-TK/GCV suicide system: a potential strategy for the treatment of bladder carcinoma

Novel treatment strategies such as gene therapy are warranted in view of the failure of current treatment approaches to cure a high percentage of patients with advanced bladder cancers. The emergence of cancer gene therapy potentially offers a number of exciting treatments. The majority of approaches involve strategies to suppress the function of activated oncogenes to restore the expression of functional tumour suppressor genes or to initiate tumour self-destruction. One gene therapy approach against tumours that holds great promise is suicide gene therapy. Herpes simplex virus thymidine kinase (HSV-TK) phosphorylates ganciclovir (GCV), which in turn interacts with cellular DNA polymerase and interferes with DNA synthesis to cause death of rapidly dividing cells. The development of an effective delivery system is absolutely critical to the usefulness and safety of gene therapy. At present, the adeno-associated virus (AAV) vector has the most promising potential in view of its non-pathogenicity, wide tropisms and long-term transgene expression in vivo. Gene therapy studies using different serotypes of recombinant AAV (rAAV) as delivery vehicles have proved rAAVs to be an effective modality of cancer gene therapy. In the present study, we investigated the suppression effect of AAV-mediated HSV-TK/GCV system on the bladder cancer cells and in mice xenograft models of bladder cancer. Our data demonstrate that rAAV-HSV-TK system controlled tumour cell growth and achieves strong antitumour efficacy in vivo. These findings provide a foundation for the development of potential targeted clinical therapies for bladder cancer in humans.     

Radiation-guided gene therapy of cancer

Gene therapy has been proposed as a means to combat cancer. However, systemic toxicity observed in preclinical trials suggested the importance of selectively targeted delivery and inducible gene expression in tumor tissues. Discovery of radiation-inducible promoter sequences provides one way to minimize inadvertent toxicity from gene therapy in normal tissues. Radiation is administered to selectively induce cytotoxic gene expression in the targeted tumor tissues. With promising results from phase II clinical trials using TNF-expressing adenovirus, it is possible to have radiation-guided gene therapy regimes once the tumor-targeted delivery has been achieved. Tumor endothelium is an attractive biological target for gene therapy, because it has the advantage of stability, accessibility, and bioavailability for therapeutic agents. Technological development of DNA microarray, proteomic profiling, and phage-displayed libraries accelerates the identification of tumor-specific endothelial biomarkers and discovery of its relevant affinity reagents for targeted delivery. The application of radiation-guided gene delivery, its amplification, as well as expression of gene therapy presents great opportunities to be employed as an alternative cancer treatment.     

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

RNA interference (RNAi)-based gene silencing is widely used in laboratories for gene function studies and also holds a great promise for developing treatments for diseases. However, in vivo delivery of RNAi therapy remains a key issue. Lentiviral vectors have been employed for stable gene transfer and gene therapy and therefore are expected to deliver a stable and durable RNAi therapy. But this does not seem to be true in some disease models. Here, we showed that lentivirus delivered short-hairpin RNA (shRNA) against human papillomavirus (HPV) E6/E7 oncogenes were effective for only 2 weeks in a cervical cancer model. However, using this vector to carry two copies of the same shRNA or two shRNAs targeting at two different but closely related genes (HPV E6 and vascular endothelial growth factor) was more effective at silencing the gene targets and inhibiting cell or even tumor growth than their single shRNA counterparts. The cancer cells treated with dual shRNA were also more sensitive to chemotherapeutic drugs than single shRNA-treated cells. These results suggest that a multi-shRNA strategy may be a more attractive approach for developing an RNAi therapy for this cancer.     

The efficacy of combination therapy using adeno-associated virus-mediated co-expression of apoptin and interleukin-24 on hepatocellular carcinoma

Multigene-based combination therapy is an effective practice in cancer gene therapy. Apoptin is a chicken anemia virus-derived, p53-independent, Bcl-2-insensitive apoptotic protein with the ability to specifically induce apoptosis in various human tumor cells. Interleukin-24 (IL-24) displays ubiquitous antitumor property and tumor-specific killing activity. Adeno-associated virus (AAV) is a promising gene delivery vehicle due to its advantage of low pathogenicity and long-term gene expression. In this study, we assessed the efficacy of combination therapy using AAV-mediated co-expression of apoptin and interleukin-24 on hepatocellular carcinoma in vitro and in vivo. Our results showed that AAV-mediated co-expression of IL-24 and apoptin significantly suppressed the growth and induced the apoptosis of HepG2 cells in vitro. Furthermore, AAV-mediated combined treatment of IL-24 and apoptin significantly suppressed tumor growth and induced apoptosis of tumor cells in xenograft nude mice. These data suggest that AAV vectors that co-express apoptin and IL-24 have great potential in cancer gene therapy.