Delivery of antiangiogenic agents for cancer gene therapy

The understanding that tumor growth and metastasis are angiogenesis dependent processes has led to interest in targeting tumor vasculature in anticancer therapy. Furthermore, recent insights into the molecular interactions that orchestrate physiologic and pathologic angiogenesis have resulted in a variety of antiangiogenic strategies. A gene therapy-mediated approach for the delivery of antiangiogenic agents has several advantages, including the potential for sustained expression. However, the choice of angiogenesis inhibitor, method of gene delivery, and target/site for transgene expression are important variables to be considered when designing this approach. Here we review the major alternatives within each of these categories and provide illustrative examples of their use in preclinical models.     

Progress in cancer gene therapy

The "First International Symposium on Genetic Anticancer Agents," which took place in Amsterdam on March 8-9, 2000, served as a forum to review the results of preclinical and clinical gene therapy studies for cancer endeavored to date. Despite the fact that gene therapy was initially conceptualized as an approach for inherited genetic disease, it is currently finding its widest employ for treating neoplastic disorders. In this regard, more than 70% of patients treated to date in human clinical gene therapy protocols have been in the context of anticancer regimens. Of note, the application of gene therapy for cancer has proceeded from the same rational basis as was originally conceptualized for inherited genetic disorders. Specifically, the molecular basis of these disorders is increasingly being understood, therapeutic genes are available, and alternative therapies are often lacking. Most recently, the field of gene therapy has enjoyed the realization of the first incontrovertible evidence of clinical benefit, for hemophilia and cardiovascular disease, in its first 15 years of human application. This recent recognition of the potential power of gene therapy, and the current lack of realizing such ends for neoplastic disease, has led to a reassessment of the field. Such a critical analysis is a necessary step in defining the means to progress the technology toward achieving the potential benefits of gene therapy for cancer.     

抗血管生成药治疗肝细胞癌的研究进展

肝细胞癌（HCC）是一种血管丰富的癌症,抗血管生成药可通过阻断血管生成因子,抑制内皮细胞扩增及预防细胞外基质和血管基底膜降解等机制而发挥治疗肝癌的作用,加上其临床相对优良的安全性可能为肝癌治疗提供了治疗新途径。     

肿瘤血管生成及抗血管生成基因治疗

肿瘤的侵袭和转移明显影响患者的预后,而肿瘤的血管生成是肿瘤生长、侵袭、转移的基本条件.因而抑制肿瘤血管生成是治疗肿瘤的关键.本文就肿瘤血管生成的调控及抗肿瘤血管生成基因治疗的研究进展作一综述.     

大肠癌基因治疗进展

大肠癌基因治疗是研究热点之一,主要包括免疫分子基因治疗、自杀基因治疗、基因缺陷纠正、抑制肿瘤血管生成基因治疗和病毒基因转导溶解肿瘤细胞等方法。现综述以上几种大肠癌基因治疗方法的研究现状和进展。     

Progress towards gene therapy for cancer

This review highlights the current strategies being employed towards gene therapy of cancer. Conceptually, the most simple diseases to treat with gene therapy would be monogenic inherited diseases, such as hemophilia. However, the vast majority of current gene therapy trials are for treatment of cancer patients, due to the recognition of gene alterations in cancer and the critical need for improvement of cancer therapy. Gene-based therapies for cancer in clinical trials include strategies that involve immuno-therapy, induction of drug sensitivity in tumor cells or resistance to chemotherapy of critical host tissues, and compensation for oncosuppressor loss or ablation of oncogenes. Two broad approaches have been used to deliver DNA to cells, a series of viral vectors and the use of plasmid DNA vectors, which have different advantages with regard to efficiency of gene transfer, ease of production and safety. Examined objectively, many of the first studies in cancer gene therapy clinical trials have provided information of critical importance for the design of more efficient second-generation protocols. Gene therapy represents one of the most important developments in oncology, however, before this can be realized as standard treatment the technical problems of gene delivery and safety must be overcome. Here we focus on methods and strategies used to achieve cancer gene therapy and the current clinical trials.     

Toxicities of antiangiogenic therapy in non-small-cell lung cancer

The addition of antiangiogenic agents has improved overall survival in a wide variety of tumor types, including non-small-cell lung cancer (NSCLC). Antibodies to the vascular endothelial growth factor (VEGF) were the first targeted agent to yield a significant improvement in overall survival when combined with first-line chemotherapy for metastatic NSCLC. Anti-VEGF antibodies and tyrosine kinase inhibitors blocking VEGF receptor (VEGFR) activity are also being investigated in pretreated NSCLC. Initial experience with anti-VEGF antibodies suggested a mild adverse event profile. However, it has become clear with additional experience that antiangiogenic agents are associated with a distinct array of toxicities, such as hemorrhage, hypertension, thromboembolic events, and proteinuria. Furthermore, an increase in chemotherapy-associated toxicities such as neutropenia has been observed with the addition of anti-VEGF antibodies. Multitargeted small-molecule inhibitors that block activity of the VEGFR tyrosine kinase are associated with fatigue and other toxicities in addition to the aforementioned class-effect toxicities, possibly because of their inhibition of multiple signaling pathways. Currently, only patients without predominant squamous cell histology are eligible to receive bevacizumab. Trials are ongoing to address the feasibility of bevacizumab in patients who were excluded from the phase III pivotal trial. Additionally, further investigation is necessary to determine risk factors for hemorrhage with antiangiogenic agents.     

乳腺癌抗血管生成治疗的研究进展

新生血管生成是恶性肿瘤的增殖过程中的关键步骤,因此抗血管生成已成为抗肿瘤治疗的重要策略和研究热点。本文就乳腺癌抗肿瘤血管生成治疗的研究背景、应用现状、未来展望作一综述。     

A role for antiangiogenic therapy in breast cancer

The success of the angiogenesis inhibitor bevacizumab, the vascular endothelial growth factor antagonist that was recently shown to significantly improve the survival of patients with metastatic colon cancer when administered in combination with conventional chemotherapy, has provided proof of principle in clinical trials that antiangiogenesis can be an important strategy in the treatment of cancer. This report reviews the contemporary therapeutic approaches for breast cancer, the essential role that angiogenesis plays in the initiation and progression of this disease, and the strategies that should be considered to make antiangiogenic therapy a successful component of breast cancer treatment.     

A role for antiangiogenic therapy in breast cancer

The success of the angiogenesis inhibitor bevacizumab, the vascular endothelial growth factor antagonist that was recently shown to significantly improve the survival of patients with metastatic colon cancer when administered in combination with conventional chemotherapy, has provided proof of principle in clinical trials that antiangiogenesis can be an important strategy in the treatment of cancer. This report reviews the contemporary therapeutic approaches for breast cancer, the essential role that angiogenesis plays in the initiation and progression of this disease, and the strategies that should be considered to make antiangiogenic therapy a successful component of breast cancer treatment.     

Progress of gene therapy for esophageal cancer in Japan

Retrovirally expressed interleukin-2 gene, granulocyte macrophage-colony stimulating factor gene, herpes simplex virus-thymidine kinase gene and p53 gene in human esophageal cancer cells showed antitumor effects in a nude mice xenotransplant model. We established a clinical protocol of gene therapy for advanced esophageal cancer using the wild type p53 gene with an adenovirus vector. In December of 2000, we began the first tumor suppressor gene therapy trial. Now, this trial, which has 9 patients. There have been no serious adverse event excluding fever and local pain. The feasibility of this treatment appears fairly good in these 9 cases. Furthermore, we developed a new method for transducing genes without a virus vector since a virus vector has several potentially unwanted properties. In vivo electroporation is a useful strategy for cancer gene therapy. Moreover, electric pulse to established solid tumors increases intracellular concentrations of chemotherapeutic agents. Transduction of the wild-type p53 gene by electroporation decreased the amount of nedaplatin required for tumor suppression. Electrochemo-gene therapy is a relatively simple method and can produce a better therapeutic effect.     

The horizon of antiangiogenic therapy for colorectal cancer

Vascular endothelial growth factor (VEGF) plays a crucial role in the growth and metastatic spread of cancer. Bevacizumab (Avastin) is the first commercially available VEGF inhibitor, earning U.S. Food and Drug Administration (FDA) approval in February 2004. In combination with fluorouracil (5-FU)-based chemotherapy, this agent significantly prolongs overall and progression-free survival of patients with metastatic colorectal cancer. This review details the emerging role of the drug, its unique side effects, and other practical considerations related to bevacizumab therapy. Ongoing trials attempting to define additional indications for bevacizumab as well as the development of other promising angiogenesis inhibitors are also reviewed.     

白细胞介素12抗肿瘤治疗进展

白细胞介素(IL)12是由巨噬细胞等抗原提呈细胞产生的具有多种生物学活性的异二聚体细胞因子,可刺激自然杀伤(NK)细胞、淋巴因子激活的杀伤细胞(LAK)细胞、细胞毒性T淋巴细胞(CTL)细胞的形成,增强机体对病原、肿瘤细胞的杀伤清除能力,诱导干扰素(INF)-γ、IL -2、IL-3、IL-8等细胞因子分泌和促进I型辅助性T细胞分化等多种生物学活性。国内外学者采用不同的治疗途径及不同的联合方案进行了大量尝试,以求获得最佳的抗肿瘤效应。     

白细胞介素12抗肿瘤治疗进展

白细胞介素（IL）12是由巨噬细胞等抗原提呈细胞产生的具有多种生物学活性的异二聚体细胞因子,可刺激自然杀伤（NK）细胞、淋巴因子激活的杀伤细胞（LAK）细胞、细胞毒性T淋巴细胞（cTL）细胞的形成,增强机体对病原、肿瘤细胞的杀伤清除能力,诱导干扰素（INF）-γ、IL-2、IL-3、IL-8等细胞因子分泌和促进Ⅰ型辅助性T细胞分化等多种生物学活性。国内外学者采用不同的治疗途径及不同的联合方案进行了大量尝试,以求获得最佳的抗肿瘤效应。     

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.     

Mouse macrophage metalloelastase gene delivery by HVJ-cationic liposomes in experimental antiangiogenic gene therapy for murine CT-26 colon cancer

We previously demonstrated that gene replacement of mouse macrophage metalloelastase (MME) into murine melanoma cells that grow rapidly and are MME deficient suppresses the primary tumor growth in vivo by halting angiogenesis. The aim of the present study was to evaluate the effectiveness of gene therapy against cancer using a cDNA-encoding MME gene. In a subcutaneous tumor model of CT-26 mouse colon cancer cells that are MME deficient, syngeneic mice repetitively treated with direct injections into the tumors of MME- hemagglutinating virus of Japan (HVJ), a type of HVJ-cationic liposome encapsulating a plasmid expressing MME, developed smaller tumors (210 +/- 47.2 mm(3) versus 925 +/- 156 mm(3) mean +/- SEM; p = 0.0004) with fewer microvessels (10.25 +/- 1.03 vs. 17.25 +/- 2.14; p = 0.03) than control mice. TUNEL staining revealed a significant increase of apoptotic cells in the MME-HVJ liposomes-treated tumors compared with control tumors. MME was effectively expressed in the s.c. tumors treated with MME-HVJ liposomes, inducing angiostatin generation in those tumors, as demonstrated by Western blot analysis. In conclusion, our study demonstrated that repeated in vivo transduction of the MME gene directly into the tumors using HVJ-cationic liposomes suppressed the tumor growth by an antiangiogenic mechanism, providing, then, a feasible strategy for gene therapy of cancer.     

The potential of antiangiogenic therapy in non-small cell lung cancer.

The long-term prognosis for patients with advanced non-small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small-molecule VEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.     

Current status and perspective of antiangiogenic therapy for cancer: urinary cancer

Angiogenesis is considered a prerequisite for solid tumor growth. Antiangiogenic therapy reduces tumor size and extends host survival in a number of preclinical animal models. However, in humans antiangiogenic therapy is a poor promoter of tumor regression and has shown minimal effect on patient survival. In urinary cancers, such as renal cell cancer, prostate cancer, and bladder cancer, advanced refractory disease is a good candidate for antiangiogenic therapy because of its resistance to ordinary chemotherapy, radiotherapy, and hormonal therapy. Unique characteristics of molecular mechanisms underlie the induction of angiogenesis in urinary cancers. In this review, we summarize these unique mechanisms and review the results of clinical trials of antiangiogenic therapy for these cancers, discussing prospects and problems relating to antiangiogenic therapy.     

厌氧菌作为肿瘤基因治疗转移载体的研究进展

实体瘤内存在低氧坏死区域，故可利用具有趋低氧特性的厌氧茵作为肿瘤基因治疗的转移载体。研究表明厌氧茵作为基因载体肿瘤靶向性较强，且使用较安全，是一种新型的基因治疗转移载体。现综述厌氧菌作为肿瘤基因治疗转移载体的研究进展。