乳腺癌的自杀基因治疗研究进展

自杀基因疗法是一种具有临床应用前景的治疗肿瘤的方法.近年来自杀基因治疗乳腺癌的研究主要集中于自杀基因系统的发现和改进,靶向基因转移载体的构建,自杀基因与其他治疗方法的联合运用,本文在这几方面作了简要综述.     

肾癌的基因治疗进展

大多数肾癌对化疗和放疗不敏感 ,预后较差 ,目前仍缺乏有效的治疗手段 ,随着基因转导技术、肿瘤免疫学、分子生物学等学科的发展 ,基因治疗成为较有前景的一种方法。应用修复抑癌基因、阻断癌基因、抗血管疗法、免疫基因治疗及自杀基因治疗等疗法治疗肾癌已取得了很大进展。     

肾癌的基因治疗进展

大多数肾癌对化疗和放疗不敏感，预后较差，目前仍缺乏有效的治疗手段，随着基因转导技术、肿瘤免疫学、分子生物学等学科的发展，基因治疗成为较有前景的一种方法。应用修复抑癌基因、阻断癌基因、抗血管疗法、免疫基因治疗及自杀基因治疗等疗法治疗肾癌已取得了很大进展。     

骨肉瘤基因治疗研究进展

随着骨肉瘤发生机制研究不断深入,骨肉瘤基因治疗技术得到很大发展.目前常用的骨肉瘤基因治疗策略有基因补偿治疗、自杀基因疗法和免疫增强疗法.近年研究发现间充质干细胞对多种肿瘤具有趋向性,可利用其携带治疗基因靶向至肿瘤部位,从而提高基因治疗效率.该文就骨肉瘤基因治疗研究进展作一综述.     

自杀基因旁观者效应的研究进展

目前世界上威胁人类健康常见的疾病之一仍然是肿瘤,人类针对肿瘤进行着孜孜不倦的研究,目前在肿瘤治疗方面,基因治疗是一个较为有前途的治疗手段,其中肿瘤自杀基因疗法是研究最为广泛的,而旁观者效应在肿瘤自杀基因疗法中起着相当重要的作用,因此,为提高自杀基因杀伤肿瘤效果,部分研究者从增强旁观者效应方面做了许多研究.故本文从增强自杀基因旁观者效应治疗肿瘤方面做一综述.     

骨肉瘤基因治疗研究进展

近年来随着分子生物学研究的进展,人们对骨肉瘤的发生机制在分子水平有了一定的认识.目前针对骨肉瘤已经开展了免疫基因治疗、反义基因治疗、抑癌基因治疗、自杀基因治疗以及联合基因治疗或联合其他疗法治疗等多种肿瘤基因治疗方法.但无论是哪种基因治疗方法均需构建能将外源基冈特异性转移至靶细胞的载体,因此有无安全、无毒的载体成为基凶治疗的瓶颈.     

胃肠道肿瘤的自杀基因治疗研究进展(文献综述)

肿瘤自杀基因疗法是一种具有潜在应用价值的肿瘤治疗方法。本文从自杀基因体系、载体构建、靶向性转导和转录、旁观者效应、联合基因疗法等几个方面着重介绍了胃肠道肿瘤自杀基因疗法的研究进展。     

胃肠道肿瘤的自杀基因治疗研究进展

肿瘤自杀基因疗法是一种具有潜在应用价值的肿瘤治疗方法,本文从自杀基因体系。载体构建、靶向性转导和转录、旁观者效应、联合基因疗法等几个方面着重介绍了胃肠道肿瘤自杀基因疗法的研究进展。     

胞嘧啶脱氨酶基因联合放射治疗恶性肿瘤的研究进展(文献综述)

以胞嘧啶脱氨酶基因为主的自杀基因治疗已日渐引起肿瘤研究者的兴趣 ,近几年出现的基因联合放疗对恶性肿瘤的治疗 ,使两者之间的优势得以互补 ,大大增强了对肿瘤治疗的效果。本文就胞嘧啶脱氨酶基因联合放疗对恶性肿瘤治疗的作用机制、基因转导方法、靶向性表达、基因显像、治疗效果等方面予以综述。     

胞嘧啶脱氨酶基因联合放射治疗恶性肿瘤的研究进展（文献综述）

以胞嘧啶脱氨酶基因为主的自杀基因治疗已日渐引起肿瘤研究者的兴趣,近几年出现的基因联合放疗对恶性肿瘤的治疗,使两者之间的优势得以互补,大大增强了对肿瘤治疗的效果。本文就胞嘧啶脱氨酶基因联合放疗对恶性肿瘤治疗的作用机制、基因转导方法、靶性表达、基因显像、治疗效果等方面予以综述。     

Possibility and future problems of gene therapy for gastric cancer]

Recently, stage-oriented surgery has been performed for gastric cancer, but a new strategy is necessary for stage IV gastric cancer. The first target of gene therapy for gastric cancer was for stage IV patients with-widespread lymph node metastases and/or peritoneal dissemination. We reported on suicide gene therapy in experimental gastric cancer induced by ENNG in the dog, and the results showed that in situ gene transfer of a suicide gene (Ad. CAGHSV-TK) followed by prodrug (GCV) treatment may be applicable not only to the primary gastric tumor, but also to lymph node metastasis. Next, we assessed the efficacy of in situ gene therapy with Ad. CAGHSV-TK/GCV in gastric cancer induced by MNNG in rats, and followed the histopathological changes in the gastric cancer and HSV-TK gene in peripheral blood for 30 days. The results showed that: 1) apoptosis preceded tissue degeneration; 2) histopathological efficacy requires 30 days after suicide gene therapy; and 3) the HSV-TK gene persisted for 30 days. Based on these studies, we speculated that combination treatment with endoscopy is possible for all early gastric cancer, i.e., endoscopic mucosal resection of the primary tumor plus suicide gene therapy for sentinel lymph node metastasis. New possible strategies for peritoneal dissemination are: 1) tumor dormancy therapy with adeno-associated virus (AAV); and 2) combination gene therapy with suicide genes plus gene transfer to provide immunotherapy.     

Gene therapy for high-grade glioma

High-grade glioma is the most frequently occurring primary brain tumor and is associated with a poor prognosis. Current treatment regimens have had only a modest effect on the progressive course despite recent advances in surgery, radiotherapy, and chemotherapy. Gene therapy for brain tumors represents a novel and promising therapeutic approach and has been investigated clinically for the last two decades. The strategies of gene therapy include suicide gene therapy, immune gene therapy, oncolytic viral therapy, tumor suppressor gene therapy, and antisense therapy. Here, we review gene therapy approaches considering the clinical results, limitations, and future directions.     

Gene therapy for gastrointestinal tract cancer: Prospects for combination treatment consisting of surgery and molecular surgery

Progress in understanding carcinogenesis has shown cancer to be a disease caused by gene abnormalities, and a variety of oncogenes and tumor suppressor genes have thus been identified. Advances in molecular biology have given us new tools for diagnosing, staging and predicting the outcome for cancer patients and gene therapy could therefore potentially revolutionize the treatment of gastrointestinal (GI) tract cancer. Progress has been made in several approaches related to genetic modification: (1) antisense oncogene and the restoration of tumor suppresor gene therapy; (2) suicide gene therapy; and (3) cancer immunotherapy. In situ in vivo gene transfer is a practical method of gene therapy for GI tract cancer. Although many hurdles need to be overcome to achieve effective gene transfer and targeting, our early results of in situ in vivo suicide gene therapy for canine gastric cancer are promising. The era of combined treatment consisting of surgery and molecular surgery for GI tract cancer is thus considered to soon be possible.     

Gene therapy and gastrointestinal cancer: concepts and clinical facts

Background: Principles of the treatment of gastrointestinal cancer with gene therapy evolved from the advent of techniques in molecular biology, from increasing insights into the molecular basis of tumorigenesis and from the need to develop more efficient treatment modalities. Any gene therapy approach has to take two major tasks into consideration: the therapeutic gene has to be delivered into the target cell population with high efficiency, specificity and safety, and has to act in a way that provides a benefit to the patient. Discussion: Data on 22 clinical trials on malignancies of the gastrointestinal tract are available. They utilize a variety of gene-delivery methods and target cell populations, and there is considerable variety among their strategies. Gene transfer is performed by injection of naked plasmid DNA and by use of DNA–liposome complexes and viral vectors. In some cases, the gene transfer is carried out ex vivo and the patients receive genetically modified cells, whereas other approaches deliver the vector to the target cell population in vivo. The theoretical concepts of gene therapy can be divided into three groups. One approach makes use of suicide genes comprising bacterial or viral genes that convert a nontoxic prodrug into a highly cytotoxic chemotherapeutic agent at the tumor site. This approach aims at higher therapeutic specificity and fewer side effects than with the systemic delivery of cytotoxic agents. The second strategy makes an attempt to invoke the immune system to destroy malignant cells. Different strategies, such as immunization with genetically modified tumor cells or transfer of new genes to T cells, are considered to have clinical benefits. The major advantage of these immunotherapeutic approaches is the systemic effect both on the primary tumor and on metastases. The third strategy evolved from the insight that cancer is a genetic disease caused by activation of oncogenes or inactivation of tumor-suppressor genes. Compensation of genetic defects by the downregulation of activated oncogenes or the restoration of tumor-suppressor-gene functions may be able to revert the malignant phenotype of cancer cells. Of the 22 gene-therapy trials, 17 trials focus on immunotherapy. Only two trials make use of suicide genes and, in three trials, a functional copy of the p53 tumor-suppressor gene was reintroduced into malignant cells. Modalities for gene transfer and the strategies underlying gene therapy will be discussed in the context of gastrointestinal malignancies and the potential benefits for patients. Received: 10 December 1998 Accepted: 25 May 1999     

Is gene therapy soon going to be used clinically in advanced cancer of the prostate?

Summary Gene transfer strategies for prostate cancer may yield promising future perspectives. In this regard, gene modified tumor vaccines, suicide gene therapy and gene replacement of nonfunctioning tumor suppressor genes are of special interest. Clinical phase I and early phase II studies with gene modified vaccines have to demonstrate the clinical implication of these new therapeutic options. Apart from this approach the development of more efficient delivery systems for in vivo gene transfer is highly desirable.      

Gene therapy for brain tumors: the fundamentals

BACKGROUND: Over the past two decades, significant advances have been made in the fields of virology and molecular biology, and in understanding the genetic alterations present in brain tumors. The knowledge gained has been exploited for use in gene therapy. OBJECTIVE: The purpose of this article is to present an introduction to the field of brain tumor gene therapy for the practicing clinician. RESULTS: A variety of gene therapy strategies have now been used in the laboratory and in clinical trials for brain tumors. They can be divided into five categories: 1) gene-directed enzyme prodrug ("suicide gene") therapy (GDEPT); 2) gene therapy designed to boost the activity of the immune system against cancer cells; 3) oncolytic virus therapy; 4) transfer of potentially therapeutic genes--such as tumor suppressor genes--into cancer cells; and 5) antisense therapy. GDEPT is the strategy that has been most extensively studied. CONCLUSIONS: To date, gene therapy has been found to be reasonably safe and concerns related to adverse events such as insertional mutagenesis have not been realized. Although patients have not been cured, the development of this therapy could still be considered to be at an early stage. Current research is addressing factors that could be limiting the successful clinical application of gene therapy, which remains an intriguing experimental option for patients with malignant brain tumors.     

Molecular Targeting of Pancreatic Disorders

Abstract During the last decade significant advances in gene therapy have made it possible to treat various pancreatic disorders in both animal models and in humans. For example, insulin gene delivery to non--cell tissues has been shown to reverse hyperglycemia in diabetic mice, and islet transplantation, based on in vitro differentiation of cells and concomitant gene targeting to prevent host autoimmune responses, has become more feasible. Additionally, introduction of the glucokinase regulatory protein and protein kinase C- have been shown to improve glucose tolerance in non-insulin-dependent diabetes mellitus animal models. Pancreatic cancer studies utilize several DNA-based strategies for tumor treatment including introduction of tumor suppressor genes, suppression of oncogenes, suicide gene/prodrug therapy, and restricted replication-competent virus therapy. Tumor-specific targeting is an important part of suicide gene therapy, and tumor-specific promoters are used for cell-specific targeting. Tumor-specific suicide gene therapy directed by the rat insulin promoter has been used to eliminate insulinoma tumors in a mouse model. This review compiles a compendium of information related to the treatment of pancreatic disorders using gene therapy.     

Current Progress in Suicide Gene Therapy for Cancer

Standard chemotherapeutic agents and ionizing radiation destroy dividing cells. Because tumor cells divide more rapidly than normal cells, there is a therapeutic index in which damage to the cancer cells is maximized while keeping the toxicity to the normal host cells acceptable. Suicide gene therapy strives to deliver genes to the cancer cells, which convert nontoxic prodrugs into active chemotherapeutic agents. With this strategy, the systemically administered prodrug is converted to the active chemotherapeutic agent only in cancer cells, thereby allowing a maximal therapeutic effect while limiting systemic toxicity. A literature search was conducted using the MEDLINE database from 1990 to 2001 to identify articles related to suicide gene therapy for cancer. A number of suicide gene systems have been identified, including the herpes simplex virus thymidine kinase gene, the cytosine deaminase gene, the varicella-zoster virus thymidine kinase gene, the nitroreductase gene, the Escherichia coli gpt gene, and the E. coli Deo gene. Various vectors, including liposomes, retroviruses, and adenoviruses, have been used to transfer these suicide genes to tumor cells. These strategies have been effective in cell culture experiments, laboratory animals, and some early clinical trials. Advances in tissue- and cell-specific delivery of suicide genes using specific promoters will improve the clinical utility of suicide gene therapy.