蛋白酶激活受体在肿瘤血管生成中的作用及其靶向抗肿瘤药物研究进展

肿瘤血管生成是肿瘤生长过程中一个重要的步骤,可以为肿瘤细胞提供氧气和营养物质,也与肿瘤细胞转移有关。目前,抗血管生成被认为是肿瘤治疗的一个重要靶点。蛋白酶激活受体（PAR）是G蛋白偶联受体家族成员之一,已被证明可以作为癌基因,在多种肿瘤细胞中高表达。研究发现,PARs可被凝血酶激活,诱导血管内皮生长因子（VEGF）表达,参与肿瘤血管生成,可作为抗肿瘤血管生成的靶点。本文主要介绍了PARs的活化机制及其在肿瘤血管生成中的作用,并对近年来靶向PARs抑制肿瘤血管生成的抗肿瘤药物的结构、药理活性的研究进展进行总结。     

uPA及其受体uPAR系统与宫颈癌关系的研究进展

肿瘤的浸润转移和血管生成与细胞外基质降解密切相关,而细胞外基质的降解与多种蛋白水解酶有关,其中尿激酶型纤维蛋白酶原激活剂（uPA）及其受体（uPAR）系统在介导基质蛋白降解过程中起重要作用。uPA/uPAR系统可能在宫颈癌细胞增殖、血管生成、浸润转移等过程中发挥重要作用。抑制uPA/uPAR系统的表达可能成为宫颈癌的防治靶点。     

叶酸靶向肿瘤免疫治疗研究进展

叶酸受体（FR）是一种通过聚糖磷脂酰肌醇（GPI）锚着于膜上的糖蛋白，对叶酸具有高度亲和力，在正常组织分布较少，而在90％以上的卵巢癌和许多上皮细胞及髓细胞来源的恶性肿瘤有过度表达。FR对叶酸偶联的药物同样具有高度亲和力，因此FR被开发为治疗肿瘤的叶酸偶联药物的选择性靶向受体。在众多有关FR靶向疗法中，FR阳性肿瘤通过免疫调节的疗法取得了显效果。     

抗体导向的酶催化前体药物疗法

目的 综述抗体导向的酶催化前体药物疗法（Antibody directed enzyme prodrug therapy,ADEPT）的研究进展,评价这种技术应用的潜力。方法检索近几年国内外研究ADEPT的相关文献,并进行分析、归纳。结果“抗体导向的酶催化前体药物疗法”是一种肿瘤靶向治疗两步策略。该策略以巧妙的设计克服了以往单抗作为药物载体的许多缺陷,通过分子与分子靶标,酶与底物（前药）的双重选择性,提高药物对肿瘤细胞的靶向性,降低毒性,克服耐药性。结论抗体导向的酶催化前体药物疗法是一种极有发展前途的肿瘤靶向疗法。     

表没食子儿茶素没食子酸酯的多靶点作用研究进展

表没食子儿茶素没食子酸酯（epigallocatechin-3-gallate,EGCG）作为绿茶中提取的多酚类化合物,具有很强的抗氧化活性。在近30年的研究中,EGCG被证实对多种疾病有治疗作用。特别是在抗肿瘤药物研究领域,EGCG的多靶点抗肿瘤作用已经被广泛认可。EGCG对多种肿瘤细胞的增殖、迁移、转化、代谢具有抑制作用,这种抑制作用主要是通过影响肿瘤发生发展过程中发挥重要作用的多个信号通路（降低信号分子的功能或表达）、影响肿瘤相关基因甲基化、影响细胞膜受体的靶向性结合等方式实现的。同时,近几年有关EGCG与临床抗肿瘤药物联合应用降低肿瘤细胞耐药性、提高药物疗效的研究也成为了多靶点药物研究领域的热点。本文主要对EGCG的多靶点、多途径抗肿瘤作用研究作一总结。     

抗血小板药物研究进展及新靶点药物的发现

抗血小板药物是预防和治疗心肌梗死和缺血性脑卒中等动脉血栓疾病的主要药物,目前应用的该类药物主要包括阿司匹林、P2Y₁₂受体拮抗剂、糖蛋白IIb/IIIa（GPIIb/IIIa）受体拮抗剂和蛋白酶激活受体（PAR1）拮抗剂等。尽管已有抗血小板药物能够在一定程度上降低动脉血栓疾病的发生,但出血副作用不容忽视。随着对血小板相关机制研究的不断深入,越来越多抗血小板药物新靶点被发现,包括蛋白酶激活受体（PARs）、血小板糖蛋白VI（GPVI）、磷脂酰肌醇激酶（PI3Kβ）和蛋白二硫键异构酶（PDI）等。综述了已上市的抗血小板药物、目前临床应用存在的问题以及以新靶点研发的研究状况。     

以尿激酶型纤溶酶原激活物系统为靶点治疗肿瘤的研究进展

目的:为靶向抑制尿激酶型纤溶酶原激活物系统(u PAs)治疗肿瘤的研究提供参考。方法:通过检索国内外研究文献及相关资料,对靶向作用于肿瘤u PAs表达的各类药物的作用靶点、效果及相关机制进行归纳、总结。结果与结论:u PAs高表达与肿瘤发生、发展及预后密切相关,目前靶向抑制u PAs的研究主要包括抑制u PAs成分的表达及降低其活性,已显示出明显的疗效。随着研究的不断深入,抑制u PAs的靶向治疗将成为最有前途的靶向治疗肿瘤的方法之一。     

新型分子靶向抗癌药物卡博替尼

随着分子靶向药物的研究及临床应用,分子靶向治疗已成为肿瘤的研究热点。卡博替尼是多靶点酪氨酸激酶抑制药,可抑制多种肿瘤相关的激酶受体,抑制肿瘤细胞生长和肿瘤血管新生,临床证实对转移性甲状腺髓样癌（MTC）有效,已获得美国食品药品管理局（FDA）批准,用于治疗晚期MTC。该文综述卡博替尼的作用机制、药动学、不良反应、药物相互作用及临床试验。     

耐甲氧西林金黄色葡萄球菌感染新型控制策略研究新进展

耐甲氧西林金黄色葡萄球菌（methicillin-resistant staphylococcus aureus,MRSA）是临床常见的多重耐药菌之一，被称为“超级细菌”。随着MRSA耐药机制的不断进化，通过传统抗生素治疗MRSA感染的困难不断增加。近年来，针对MRSA感染的新型控制策略从各个层面不断深入。纳米材料的独特结构具有抗菌活性，也可作为一种高效的抗菌药物输送载体。光动力疗法通过光激活光敏剂（photosensitizer,PS）与分子氧或底物作用产生活性氧（reactive oxygen species,ROS）促进细胞氧化应激。中草药多种机制的抗菌特性已经被广泛证实。免疫疗法在对抗MRSA的免疫逃逸机制、多价疫苗和混合抗体的使用取得了突破。以mecA基因为代表的基因靶点正在不断被发掘。靶向硫醇依赖的氧化还原系统（thiol-dependent redox system,TDRS）尤其是硫氧还蛋白系统（thioredoxin system,Trx system）的新型候选抗菌化合物将是未来充满潜力的生力军。本文将MRSA的新型控制策略进行综述和展望。     

靶向间皮素免疫治疗实体瘤的研究进展

间皮素（Mesothelin）是一种肿瘤相关抗原,这一糖蛋白在超过30%的肿瘤组织中高表达,仅在少量正常组织中低水平表达,是目前研究较多的癌症免疫治疗靶点。目前有多种靶向Mesothelin的免疫治疗产品在临床试验中显示出很好的安全性,其中细胞治疗近年来发展最为迅速。本文将从Mesothelin的生物学特性、靶向Mesothelin免疫治疗药物的临床试验结果、Mesothelin CAR-T细胞免疫治疗面临的挑战和应对策略等几个方面,介绍以Mesothelin为靶点的实体瘤免疫治疗研究进展。     

The urokinase receptor as a potential target in cancer therapy

The glycolipid-anchored receptor for urokinase-type plasminogen activator (uPAR) is essential for cell-surface associated plasminogen activation and is overexpressed at the invasive tumor-stromal microenvironment in many human cancers. In line with this, uPAR and uPA levels in both resected tumor tissue and plasma are of independent prognostic significance for patient survival in several types of human cancer. As the expression of both uPAR and its cognate protease ligand thus appears to be correlated with tumor malignancy, the uPA-uPAR interaction represents an attractive target for the development of either antagonists with possible anti-invasive effects or cytotoxic agents with anti-tumor effects. In this review we discuss recent achievements in the development of protein and peptide based drug candidates targeting uPAR. The majority of these compounds has been optimized for human uPAR and exhibits a pronounced species-specificity showing little or no reactivity with murine uPAR. This evidently complicates their application in preclinical intervention studies, since an intimate interplay between the tumor and its associated stroma is a distinct feature of the invasive phenotype of many human cancers. The virtues and drawbacks of various mouse tumor models as surrogates for human cancer are also discussed in relation to uPAR targeting.     

Peptides and small molecules targeting the plasminogen activation system: towards prophylactic anti-metastasis drugs for breast cancer

Breast cancer is the most common malignancy afflicting Western women today and is responsible for many deaths due to metastatic disease. Upregulation of the plasminogen-activation system (PAS) has been shown to correlate with poor prognosis in metastatic breast cancer and targeting this system represents an attractive strategy for the development of anti-metastasis prophylactic drugs. Two promising classes of PAS-targeting agents are inhibitors of the serine protease activity of urokinase plasminogen activator (uPA) and antagonists of the interaction of uPA with its cell surface receptor (uPAR). This review begins with a brief overview of the role of PAS in cancer metastasis before describing in detail a subset of the small molecules and peptides from the patent literature that target either uPA activity or uPA/uPAR interactions for use as anti-metastasis drugs.     

抗体偶联药物及其体内外代谢的研究进展

抗体偶联药物（ADC）是由单克隆抗体和细胞毒性有效载荷通过连接子偶联而成,结合了单克隆抗体的高特异性靶向能力和细胞毒活性小分子高效杀伤作用的优点,实现了对癌细胞的精准高效清除,已成为抗癌药物研发的热点之一。自2000年美国食品药品监督管理局（FDA）批准第一个ADC药物吉妥珠单抗（Mylotarg）以来,迄今全球已有14个ADC药物获批上市。这类新型的抗癌药物正引领癌症靶向治疗的新时代。基于ADC药物的构建核心和抗肿瘤作用机制,对ADC药物的体内外代谢的研究进展进行综述,以期从代谢角度为ADC药物的设计、开发、临床前药理、毒理及后续研究提供参考。     

靶向血管内皮生长因子及其受体的抗肿瘤药物研究进展

血管生成对肿瘤的生长和转移起着关键作用,血管内皮生长因子（VEGF）及其受体信号通路是调节肿瘤新生血管生成的重要途径,因此,近年来以VEGF及其受体为作用靶标的抗肿瘤血管生成治疗已经成为研究热点,目前已有多种药物上市或处于临床试验阶段。本文主要综述了VEGF及其受体在肿瘤血管生成调节机制中的作用,同时着重介绍靶向VEGF及其受体的抗肿瘤药物的新近研究进展、临床应用及存在的问题。     

肿瘤血管生成机制及抗肿瘤血管新生的靶向药物研究进展

抗肿瘤血管新生治疗是以血管内皮细胞为靶点,通过降低血管活性因子的活性、抑制内皮细胞增殖和迁移、改变肿瘤生长微环境,从而抑制肿瘤生长过程中的血管新生,切断肿瘤的供养,最终达到遏制肿瘤生长和转移的目的,是一种全新的靶向肿瘤治疗方法.该方法具有高效特异性、不易产生耐药性、药物易于到达靶部位和毒副作用小等优点,可以有效地抑制肿瘤的转移和复发,现在已成为抗肿瘤血管生成药物研究的热点之一,该文综述了肿瘤血管生成的机制及抗血管新生治疗药物的最新研究进展.     

Nitroimidazoles as anti-tumor agents

At present cancer treatment is still a confusing problem. Great progress has been made in anti-tumor agents since a series of small molecules are approved by FDA as anti-tumor drugs. Nitroimidazoles is a kind of radiosensitizer with multiple bioactivities used in cancer treatment since 1950s. In this review, we focus on the development of nitroimidazoles as radiosensitizer, bio-reductive prodrug and other types of anti-tumor agents for cancer therapy, and the mechanism of acting as anti-tumor agents. Finally, we also discuss the prospect and developmental trend of nitroimidazoles as anti-tumor agents.     

Virosome: a novel vector to enable multi-modal strategies for cancer therapy

Despite advancements in treatments, cancer remains a life-threatening disease that is resistant to therapy. Single-modal cancer therapy is often insufficient to provide complete remission. A revolution in cancer therapy may someday be provided by vector-based gene and drug delivery systems. However, it remains difficult to achieve this aim because viral and non-viral vectors have their own advantages and limitations. To overcome these limitations, virosomes have been constructed by combining viral components with non-viral vectors or by using pseudovirions without viral genome replication. Viruses, such as influenza virus, HVJ (hemagglutinating virus of Japan; Sendai virus) and hepatitis B virus, have been used in the construction of virosomes. The HVJ-derived vector is particularly promising due to its highly efficient delivery of DNA, siRNA, proteins and anti-cancer drugs. Furthermore, the HVJ envelope (HVJ-E) vector has intrinsic anti-tumor activities including the activation of multiple anti-tumor immunities and the induction of cancer-selective apoptosis. HVJ-E is currently being clinically used for the treatment of melanoma. A promising multi-modal cancer therapy will be achieved when virosomes with intrinsic anti-tumor activities are utilized as vectors for the delivery of anti-tumor drugs and genes.     

Non-apoptotic cell death-based cancer therapy:Molecular mechanism,pharmacological modulators,and nanomedicineOA

As an emerging cancer therapeutic target,non-apoptotic cell death such as ferroptosis,necroptosis and pyroptosis,etc.,has revealed significant potential in cancer treatment for bypassing apoptosis to enhance the undermined therapeutic efficacy triggered by apoptosis resistance.A variety of anticancer drugs,synthesized compounds and natural products have been proven recently to induce non-apoptotic cell death and exhibit excellent anti-tumor effects.Moreover,the convergence of nanotechnology with...     

Ligand-based targeted therapy for cancer tissue

Background: Limited accessibility of drugs to the tumor tissues, the requirement of high doses, intolerable cytotoxicity, the development of multiple drug resistance and non-specific targeting are obstacles to the clinical use of cancer drugs and cancer therapy. Objective: Drug delivery through carrier systems to cancerous tissue is no longer simply wrapping up cancer drugs in a new formulation for different routes of delivery, rather the focus is on targeted cancer therapy. Methods: This review summarizes the exploitation of drug-loaded nanocarrier conjugates with various targeting moieties for the delivery and targeting of anticancer drugs and describes the current status of and challenges in the field of nanocarrier-aided drug delivery and drug targeting. Conclusion: The discovery of targeting ligand to cancer cells and the development of ligand-targeted therapy will help us to improve therapeutic efficacy and reduce side effects. Unlike other forms of therapy, it will allow us to maintain quality of life for patients, while efficiently attacking the cancer tissue. It indicates that ligands have a pivotal role in cancer cell targeting.