转移性结直肠癌抗血管生成靶向治疗的研究进展

近年来,由于各种新的化疗药物及分子靶向药物的使用,转移性结直肠癌(metastatic colorectal cancer,m CRC)的个体化治疗逐步取得了重要的成果。研究表明,抗血管生成靶向药物与化疗药物的联合使用作为转移性结直肠癌的一线治疗方案,可明显改善治疗效果,延长患者的生存时间。血管内皮生长因子(vascularendothelial growth factor,VEGF)是肿瘤血管生成过程中最主要的因子。贝伐单抗是通过基因工程技术得到的针对血管内皮生长因子-A(VEGF-A)的单克隆抗体,作为抗血管生成靶向药物用于转移性结直肠癌的临床治疗。本文对近年来转移性结直肠癌的抗血管生成靶向治疗,尤其是贝伐单抗治疗的相关研究进展进行综述并展望未来抗血管生成靶向治疗的发展前景。     

抑制血管生成治疗肿瘤的策略和展望

新生血管生成是绝大多数肿瘤得以生长和转移的必要前提。所以 ,通过抑制肿瘤血管生成来抑制肿瘤是非常有前途的一种方法 ,有望发展成为一种新型的癌症疗法。主要可以分为两大类 :一是通过抑制促血管生成信号或扩大抑制血管生成因子的作用来干扰肿瘤新生血管的形成过程 ,这领域的广泛研究已经发现了一系列促血管生成因子及其抑制剂和血管生成抑制因子 ;二是利用肿瘤血管与正常血管的差别来携带杀伤性药物直接特异性破坏已形成的肿瘤血管 ;另外 ,内皮细胞及其前体细胞制成疫苗也可起到直接杀伤作用。到目前为止 ,虽然很多抑制肿瘤血管的药物已经被用于临床试验 ,但结果往往不尽如人意 ,从长远来看 ,需要更有效的治疗方法。包括抗血管基因治疗策略 ,靶向药物导入系统的研究 ,以及抗血管生成药物和免疫疗法、化疗和放射治疗的联合应用都在探讨中。随着肿瘤模型评估系统的发展 ,抗血管治疗肿瘤的方法在不久的将来一定会广泛进入临床应用。     

抗肿瘤血管生成治疗的研究进展及应对策略

抗血管生成疗法作为癌症治疗的重要方法之一,能够显著抑制肿瘤的生长与转移。然而,在临床应用中仍无法避免抗血管生成药物耐药性的产生,且目前对其耐药机制的研究尚不完善,严重阻碍了临床治疗进程。因此,基于抗血管生成药物耐药机制的研究,寻找新的靶点,以及整合新的治疗方案,对于改善肿瘤的临床治疗效果意义重大。基于此,本文主要从血管生成在肿瘤发展中的作用机制、抗血管生成治疗药物的应用现状及其介导的耐药机制、未来的研究策略等方面综述了抗肿瘤血管生成治疗的最新研究进展。     

内皮抑素及其在抗肿瘤中的应用

内皮抑素是一种抗血管生成的抑制因子,它特异性地作用于新生微血管的内皮细胞,其水平与肿瘤血管生成有着明显的相关性。体内外的研究均表明,内皮抑素具有无毒副作用、不容易产生耐药性和易达到有效药物浓度等优点。我们简要综述了内皮抑素的特性、作用机制,及其在抗肿瘤应用等方面的研究进展。     

人血管生成抑制素抑瘤研究进展

肿瘤的发展和转移需要新生血管的形成。人血管生成抑制素是近年发现的能够专一性抑制血管内皮细胞的内皮抑制因子。大量研究表明,在体外用血管生成抑制素处理血管内皮细胞可以抑制新生血管的形成,在体内单独使用血管生成抑制素,或者将血管生成抑制素与其他物质如基质金属蛋白酶、尿激酶联合处理荷瘤小鼠,可以降低小鼠体内肿瘤组织新生血管密度,抑制肿瘤的生长和肿瘤细胞的迁移。简要综述了血管生成抑制素抑制肿瘤生长和转移及其作用机理。     

具新生血管抑制及血管阻断双重作用的肿瘤血管靶向药物研究进展

以血管新生抑制剂和血管阻断剂为代表的肿瘤血管靶向药物作为一种新的抗肿瘤疗法,其研究与开发已取得显著进展,尤其是二者联用已在临床实践中获得更好疗效。因而,近年来具有新生血管抑制和血管阻断双重作用的肿瘤血管靶向药物研究备受关注。这种具双重作用的肿瘤血管靶向药物因同时保持了血管新生抑制剂和血管阻断剂的各自作用特点,在临床肿瘤治疗上更具优势,不仅能一药多靶,增强抗肿瘤疗效,同时还可降低用药剂量,减少毒副作用,提高用药耐受性,故临床应用前景广阔。综述新生血管抑制剂和血管阻断剂的作用机制及特点,介绍具代表性的兼有新生血管抑制和血管阻断双重作用的肿瘤血管靶向药物研究进展。     

人血管内皮抑制素在毕赤酵母中的表达纯化及活性测定

血管内皮抑制素是胶原ⅩⅧ C-末端的一个片段,是一个有效的血管生成抑制因子。本文克隆了人血管内皮抑制素的基因,并用毕赤酵母进行表达,表达量为50.5 mg/L。发酵液上清经SP Sepharose Fast Flow凝胶一步层析,产物纯度达到98%以上,纯化收率达到95%以上。毕赤酵母分泌表达的人血管内皮抑制素具有免疫活性;能明显抑制鸡胚尿囊膜新生血管的生长;并且能特异性地抑制bFGF刺激的人微血管内皮细的迁移,达到抑制效果为50%时所需的蛋白浓度（IC50）为0.4μg/ml。本研究为应用人血管内皮抑制素治疗肿瘤奠定了初步实验基础。     

癌抑素(canstatin)在肿瘤治疗中的研究现状

癌抑素(canstatin,Cans)是继血管生成抑素(angiostatin)、内皮抑素(endostatin)和肿瘤抑素(tumstatin)之后,新近发现的一种内源性肿瘤血管生成抑制因子,因其具有高效的抗肿瘤血管形成活性而成为肿瘤治疗中的研究热点。本文就Cans的结构、功能、作用机制及在肿瘤治疗中的研究进展作一综述。     

以VEGF/VEGFR 为靶点的肺癌治疗药物研究进展

目的:论述以血管内皮生成因子(VEGF)及其受体VEGFR为靶点的肺癌的研究现状,探讨VEGF及VEGFR与肺癌发生及发展的关系,为肺癌抗血管生成的治疗提供新的药物作用途径。方法:依据近年国内外的相关文献,进行归纳和分析,对VEGF及肺癌发生相关系统进行研究,并在此基础上,提出肺癌抗血管治疗的新思路。结果:研究发现,在肺癌的发生及发展过程中,VEGF出现过量表达。为达到抑制其促血管生成的作用,以VEGF/VEGFR为靶点,研制抑制VEGF活性的药物或干扰VEGFR的药物,可在一定程度上实现通过抑制相关抗血管生成治疗肺癌的目的。结论:利用新的抗血管途径有望在肺癌治疗中研发出新药,提高肺癌治疗效果。     

血管生成抑制素作用机理的研究进展

血管生成抑制素(angiostatin)是纤溶酶原(plasminogen)在体内的天然水解产物,能够有效抑制血管内皮细胞的增殖、迁移和管状结构的形成而参与对血管生成过程(angiogenesis)的调节。血管生成是指从已经存在的血管生长出新的分枝血管的过程。该过程在成体组织并不活跃,然而在某些病理条件下如伤口愈合、炎症、肿瘤的生长和恶性转移时却常常伴随活跃的血管生成过程。血管生成抑制素对血管生成的抑制作用,提示其作为一种特异性的针对血管内皮细胞的药物治疗与血管生成有关的一些疾病,如肿瘤的可能性。本文主要介绍近年来关于Angiostatin作用机理的研究进展以及其作为治疗药物的应用前景。     

In-silico network-based analysis of drugs used against COVID-19: Human well-being study

IntroductionResearchers worldwide with great endeavor searching and repurpose drugs might be potentially useful in fighting newly emerged coronavirus. These drugs show inhibition but also show side effects and complications too. On December 27, 2020, 80,926,235 cases have been reported worldwide. Specifically, in Pakistan, 471,335 has been reported with inconsiderable deaths.Problem statementIdentification of COVID-19 drugs pathway through drug-gene and gene−gene interaction to find out the most important genes involved in the pathway to deal with the actual cause of side effects beyond the beneficent effects of the drugs.MethodologyThe medicines used to treat COVID-19 are retrieved from the Drug Bank. The drug-gene interaction was performed using the Drug Gene Interaction Database to check the relation between the genes and the drugs. The networks of genes are developed by Gene MANIA, while Cytoscape is used to check the active functional association of the targeted gene. The developed systems cross-validated using the EnrichNet tool and identify drug genes'' concerned pathways using Reactome and STRING.ResultsFive drugs Azithromycin, Bevacizumab, CQ, HCQ, and Lopinavir, are retrieved. The drug-gene interaction shows several genes that are targeted by the drug. Gene MANIA interaction network shows the functional association of the genes like co-expression, physical interaction, predicted, genetic interaction, co-localization, and shared protein domains.ConclusionOur study suggests the pathways for each drug in which targeted genes and medicines play a crucial role, which will help experts in-vitro overcome and deal with the side effects of these drugs, as we find out the in-silico gene analysis for the COVID-19 drugs.     

Recombinant Human Endostatin Endostar Suppresses Angiogenesis and Lymphangiogenesis of Malignant Pleural Effusion in Mice

Background

Malignant pleural effusion (MPE) is a common complication of lung cancer. One widely used treatment for MPE is Endostar, a recombined humanized endostatin based treatment. However, the mechanism of this treatment is still unclear. The aim of this study was to investigate the effects of Endostar in mice with MPE.

Methods and Materials

Lewis lung carcinoma (LLC) cell line expressing enhanced green fluorescent protein (EGFP) was injected into pleural cavity to establish MPE mice model. Mice were randomly divided into four groups. High dose of Endostar (30 mg/kg), low dose of Endostar (8 mg/kg), normal saline, or Bevacizumab (5 mg/kg) was respectively injected into pleural cavity three times with 3-day interval in each group. Transverse computed tomography (CT) was performed to observe pleural fluid formation 14 days after LLC cells injection. Mice were anesthetized and sacrificed 3 days after final administration. The volume of pleural effusion n was measured using 1 ml syringe. Micro blood vessel density (MVD), Lymphatic micro vessel density (LMVD), the expression level of vascular endothelial growth factor A (VEGF-A) and VEGF-C were observed by immunohistochemistry (IHC) staining.

Results

The volume of pleural effusion as well as the number of pleural tumor foci, MVD and the expression of VEGF-A were significantly reduced in high dose of Endostar treat group. More importantly, LMVD and the expression of VEGF-C were markedly lower in treat group than those in the other three control groups.

Conclusion

Our work demonstrated that Endostar played an efficient anti-cancer role in MPE through its suppressive effect on angiogenesis and lymphangiogenesis, which provided a certain theoretical basis for the effectiveness of Endostar on the MPE treatment.     

Adjuvant therapy for periampullary carcinoma and the significance of histopathological typing: A systematic review

ObjectiveThis review investigates the role of adjuvant therapy (AT) and the importance of histopathological typing in periampullary carcinoma (PAC) treatment.BackgroundPAC is a relatively rare gastrointestinal malignancy. The regimen and effect of AT in PAC are still controversial. However, there is a treatment based on histopathological types (pancreaticobiliary-type, PB-type or intestinal-type, IN-type), but there are no clear guidelines indicating that typing can be used to guide the selection of AT drugs.MethodsA literature search of PubMed and Web of Science databases was conducted for studies published from January 2001 to August 2021 on the use of AT in PAC.ResultsA total of 75 studies were included in this review. According to existing studies, AT for PAC is mostly based on 5-FU or gemcitabine, but the effect is unknown. However, when PAC is classified into different histopathological types, AT with gemcitabine is beneficial for patients with the PB-type of PAC, while 5-FU-based AT is beneficial for patients with the IN-type of PAC. In addition, the benefits of AT are more pronounced in patients with a high-risk disease, such as patients with stage II/III, T3/T4 tumors, or positive lymph node involvement. There are few studies on targeted therapy and immunotherapy for PAC.ConclusionsThis review suggests that AT has potential survival benefits, especially when based on the histopathologic type that helps the choice of drugs during AT in PAC patients.     

Systematic review and meta-analysis of Endostar (rh-endostatin) combined with chemotherapy versus chemotherapy alone for treating advanced non-small cell lung cancer

ABSTRACT: BACKGROUND: Many studies have investigated the efficacy of Endostar combined with platinum-based doublet chemotherapy (PBDC) versus PBDC alone for treating advanced non-small cell lung cancer (NSCLC). This study is a meta-analysis of available evidence. METHODS: Fifteen studies reporting Endostar combined with PBDC versus PBDC alone for treating advanced NSCLC were reviewed. Pooled odds ratios and hazard ratio with 95% confidence intervals were calculated using either the fixed effects model or random effects model. RESULTS: The overall response rate (ORR) and disease control rate (DCR) of Endostar combined with PBDC for treating NSCLC were significantly higher than those of PBDC alone, with 14.7% and 13.5% improvement, respectively (P < 0.00001). In addition, the time to progression (TTP) and quality of life (QOL) were improved after the treatment of Endostar combined with PBDC (P < 0.00001). The main adverse effects found in this review were hematological reactions, hepatic toxicity, and nausea/vomiting. Endostar combined with PBDC had a similar incidence of adverse reactions compared with PBDC alone (P < 0.05). CONCLUSIONS: Endostar combined with PBDC was associated with higher RR, DCR, and TTP as well as superior QOL profiles compared with PBDC alone. Endostar combined with PBDC had a similar incidence of adverse reactions compared with PBDC alone.     

The use of calorimetry in the biophysical characterization of small molecule alkaloids binding to RNA structures

BackgroundRNA has now emerged as a potential target for therapeutic intervention. RNA targeted drug design requires detailed thermodynamic characterization that provides new insights into the interactions and this together with structural data, may be used in rational drug design. The use of calorimetry to characterize small molecule–RNA interactions has emerged as a reliable and sensitive tool after the recent advancements in biocalorimetry.Scope of the reviewThis review summarizes the recent advancements in thermodynamic characterization of small molecules, particularly some natural alkaloids binding to various RNA structures. Thermodynamic characterization provides information that can supplement structural data leading to more effective drug development protocols.Major conclusionsThis review provides a concise report on the use of isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC) techniques in characterizing small molecules, mostly alkaloids–RNA interactions with particular reference to binding of tRNA, single stranded RNA, double stranded RNA, poly(A), triplex RNA.General significanceIt is now apparent that a combination of structural and thermodynamic data is essential for rational design of specific RNA targeted drugs. Recent advancements in biocalorimetry instrumentation have led to detailed understanding of the thermodynamics of small molecules binding to various RNA structures paving the path for the development of many new natural and synthetic molecules as specific binders to various RNA structures. RNA targeted drug design, that remained unexplored, will immensely benefit from the calorimetric studies leading to the development of effective drugs for many diseases. This article is part of a Special Issue entitled Microcalorimetry in the BioSciences — Principles and Applications, edited by Fadi Bou-Abdallah.     

非小细胞肺癌EGFR-TKIs治疗及PET分子成像的研究进展

表皮生长因子受体(epithelial growth factor receptor,EGFR)信号转导通路在非小细胞肺癌(Non-Small Cell Lung Cancer,NSCLC)中发挥重要作用,尤其胞内酪氨酸激酶结构域的突变状态决定了目前NSCLC的靶向治疗。针对EGFR突变的分子靶向药物表皮生长因子受体酪氨酸激酶抑制剂(epithelial growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)已开发并应用于NSCLC的治疗。在治疗过程中,EGFR的突变状态随时间发生动态变化,因此精准掌握EGFR的突变状态是靶向治疗方案制定、优化的关键。PET分子成像可在细胞和分子水平,对在体生物活动的发生、发展过程进行实时成像,使实时、在体揭示EGFR的突变状态成为可能。因此,多种以TKIs为前体标记放射性核素作为靶向肿瘤突变EGFR胞内段分子成像探针的研究逐渐增多。本文就EGFR-TKIs在NSCLC治疗及相关PET分子成像方面的研究进展进行综述。     

Liposomes targeting tumour stromal cells

Abstract

Liposomes have found clinical application in cancer therapy in the delivery of cytostatic agents. As a result of the targeted delivery of these toxic molecules to the tumour cells coupled to avoidance of toxicity-sensitive tissues, the therapeutic window is widened. Over the past years the focus of cancer therapy has shifted towards the stromal cells that are present in the tumour. It appears that clinically relevant tumours have acquired the ability to modulate the microenvironment in such a way that a chronic pro-inflammatory and pro-angiogenic state is achieved that contributes to invasion and metastasis and continued proliferation. Over the past years, liposomal formulations have been designed that target key stromal cell types that contribute to tumour growth. At the same time, many promising cell types have not been targeted yet and most of the studies employ drugs that aim at depleting stromal cells rather than modulating their activity towards an anti-tumour phenotype. In this review these target cell types will be addressed. Complementing these targeted formulations with the appropriate drugs to optimally suppress tumour-promoting signals while preserving anti-tumour action will be the challenge for the future.     

Therapeutic effect of small molecule targeting drug apatinib on gastric cancer and its role in prognosis and anti-infection mechanism

ObjectiveTo investigate the effect of apatinib when treating advanced gastric cancer (GC) as well as the mechanism of preventing infection. Methods: From January 2017 to December 2018, 100 advanced GC patients had failed to receive second-line or above treatment in XX Hospital were divided into two groups according to the experimental requirements: the experimental group and the blank group. The experimental group was treated with small molecule targeted drug apatinib, while the blank group was only treated with ordinary drugs. After 4 weeks of treatment, the diagnosis and evaluation were carried out every eight weeks. In this study, the mechanism of infection prevention and prognosis was studied through the internal treatment of GC patients with apatinib. Results: until the end of the fourth week, a significant difference can be seen in the treatment effect between the experimental group as well as the blank group. In the experimental group, the proportion of partial remission + disease stability reached about 73%, while that in the blank group was only about 33%. In addition, apatinib was better than the blank group in the control of adverse reactions like hypertension, proteinuria, myelosuppression as well as diarrhea. In addition, apatinib was better than the blank group when treating AFP positive GC. In terms of the therapeutic effect of apatinib, it is much better than that of the negative group. In addition, apatinib is also better than the blank group in drug resistance for GC patients. It is found that apatinib’s anti infection mechanism is to prevent the phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) as well as stop the downstream signal pathway, so as to inhibit the tumor angiogenesis, tumor growth and metastasis, so as to achieve treatment and reduce the probability of infection. Conclusion: the therapeutic effect of small molecule targeting drug apatinib on gastric cancer is better than that of other drugs, whether in therapeutic effect, drug resistance, adverse reactions or infection control. This study has important reference significance for the follow-up treatment of apatinib and cancer.     

Mesenchymal stromal cell function is not affected by drugs used in the treatment of inflammatory bowel disease

Background and aimsMesenchymal stromal cells (MSC) have both multilineage differentiation capacity and immunosuppressive properties. Promising results with MSC administration have been obtained in experimental colitis. Clinical application of MSC for the treatment of inflammatory bowel disease (IBD) is currently under investigation in phase I–III trials in patients with past or concurrent immunomodulating therapy. However, little is known about MSC interactions with these immunosuppressive drugs. To address this issue we studied the combined effect of MSC and IBD drugs in in vitro functionality assaysMethodsThe effects of azathioprine, methotrexate, 6-mercaptopurine and anti-tumor necrosis factor (TNF)-α on MSC phenotype, survival, differentiation capacity and immunosuppressive capacity were studiedResultsMSC exposed to physiologically relevant concentrations of IBD drugs displayed a normal morphology and fulfilled phenotypic and functional criteria for MSC. Differentiation into adipocyte and osteocyte lineages was not affected and cells exhibited normal survival after exposure to the various drugs. MSC suppression of peripheral blood mononuclear cell (PBMC) proliferation in vitro was not hampered by IBD drugs. In fact, in the presence of 6-mercaptopurine and anti-TNF-α antibodies, the inhibitory effect of this drug alone was enhanced, suggesting an additive effect of pharmacotherapy and MSC treatmentConclusionsThis study demonstrates that, in vitro, MSC phenotype and function are not affected by therapeutic concentrations of drugs commonly used in the treatment of IBD. These findings are important for the potential clinical use of MSC in combination with immunomodulating drugs and anti-TNF-α therapy.     

The inhibitory effects of Endostar combined with chemotherapy on human esophageal squamous cell carcinoma xenograft in mice

The purpose of this study was to investigate the efficacy of Endostar combined with chemotherapy on human esophageal squamous cell carcinoma Eca-109 in mice. The tumor xenograft models were established and randomly assigned to 4 groups: control group, Endostar group (1.5?mg/kg?day, once daily for 3?weeks), chemotherapy group (Paclitaxel 10?mg/kg?day, Cisplatin 5?mg/kg?day, for 1, 7, 14, 21?days), and chemotherapy?+?Endostar group (combination). The length and width of tumor were measured and the tumor volumes (cm³) were calculated every other day. Three weeks later, the mice were executed, and the tumor tissues were collected to weigh and analyse the histopathology and proliferation for tumor xenograft. The results demonstrated that the tumor volumes and weight in chemotherapy?+?Endostar group were significantly lower than that in other three groups. Meanwhile, the cell proliferation of tumor xenograft in combined treatment group was significantly lower than that in other three groups. It was concluded that Endostar combined with chemotherapy could obviously enhance the inhibitory effect on esophageal squamous cell carcinoma Eca-109 in mice.