抗肿瘤活性的肝素衍生物研究进展

在应用肝素及低分子量肝素(LMWH)防治肿瘤患者血栓栓塞性并发症时发现它们还具有显著的抗肿瘤活性,但其强大的抗凝活性成为抗肿瘤药物应用时的制约因素。对肝素进行化学修饰或将其与其他化合物偶联可获得抗凝活性低、抗肿瘤活性高的肝素衍生物。肝素衍生物的抗肿瘤机制有抑制类肝素酶活性、抑制P、L选择素介导的细胞间相互作用及抑制血管生长因子活性等。类肝素酶降解硫酸乙酰肝素(HS)侧链与肿瘤转移及肿瘤血管生成密切相关,P、L选择素介导的细胞间相互作用对肿瘤细胞的血源性转移过程有重要作用,血管生长因子所触发的血管生成是肿瘤生长、转移的必要条件。不同结构的肝素衍生物其抗肿瘤机制不完全相同。文章对抗肿瘤活性肝素衍生物的结构及其抗肿瘤机制作了综述。     

重组人血管内皮抑素联合放化疗治疗宫颈癌的疗效分析

<正>近年来,抗血管生成已成为治疗肿瘤侵袭和转移的一个新的研究领域。相关研究表明[1],内皮抑素在肿瘤血管生成中的诸多环节中发挥着重要作用,可间接导致肿瘤细胞休眠或退缩。重组人血管内皮抑素(Endostar,商品名:恩度)是我国在内皮抑素的基础上,自主研发的新型抗血管形成的抗肿瘤靶向治疗药物。大量研究表明~[2,3],对肺癌、结肠癌、胃癌、肝癌等多种肿瘤均有明显疗效,美国国立综合癌症网络(NCCN)、     

查尔酮衍生物抑制肿瘤活性的机制研究进展

随着对抗肿瘤靶向药物的研究,查尔酮衍生物因其广泛的生物活性和高效低毒的特点成为研究热点。本文综述了近年来发现的查尔酮衍生物及其主要靶点和信号通路,如阻滞细胞周期相关蛋白及信号通路、诱导肿瘤细胞凋亡信号通路和抑制肿瘤血管生成信号通路等,为多靶点新型抗肿瘤查尔酮衍生物的筛选及结构改造提供参考。     

内皮抑素在肺癌治疗中的应用

1971年Folkman首次发现肿瘤的生长依赖于血管生成,肿瘤细胞通过血管获得生长所需营养,血管为肿瘤转移提供通道,从此抗血管生成为肿瘤的治疗的领域。1997年O’Reilly等首先发现内皮抑素（endostatin）能特异地抑制内皮细胞增殖和迁移,进而可以抑制新生血管的生成,这为抑制肿瘤的侵袭、转移找到了新的思路。多年来,国内外学者开展的许多有关内皮抑素的基础和临床研究都表明其具有独特的抗肿瘤活性。现将近年来内皮抑素在肺癌治疗中的应用综述如下。     

重组人内抑素的抗肿瘤活性

目的观察重组人内抑素抗肿瘤活性及对血管内皮细胞增殖的抑制作用。方法用人癌裸鼠移植性肿瘤及小鼠移植性肿瘤模型对重组人内抑素进行抗肿瘤药效学观察,用MTT法观察其对血管内皮细胞及肿瘤细胞增殖的抑制作用。结果重组人内抑素,可明显抑制人胃癌BGC803和人乳腺癌B37裸鼠移植性肿瘤的生长,对小鼠肝癌H22实体瘤亦呈一定的抑制作用。MTT试验结果显示重组人内抑素可抑制人胎脐静脉血管内皮细胞ECV304的增殖,对人结肠癌HCT-8等肿瘤细胞的增殖无影响。结论重组人内抑素具有较强的抗肿瘤作用,其作用机理可能与抑制血管内皮细胞增殖、抑制肿瘤新生血管形成有关。     

肝素与硫酸乙酰肝素相关抗肿瘤药物的研究进展

随着对葡糖胺聚糖(glycosaminoglycans,GAGs)的结构和相关作用机制研究不断深化,硫酸乙酰肝素(heparan sul-fate,HS)及其结构类似物在抗肿瘤侵袭转移、抗肿瘤血管生成以及抗炎等方面的研究也成为热点。在以往研究中发现肝素,尤其是低分子量肝素(low molecular weight heparin,LMWHs)对肿瘤有一定的抑制作用。该文综述了肝素和HS抗肿瘤活性关键结构和相关机制的研究进展,肝素类似物有望成为新的抗肿瘤药物。     

抗肿瘤血管新药的研究进展

目前肿瘤血管靶向治疗新药的研究主要集中在两个方向,即肿瘤血管生成抑制剂(tumor angiogenesis inhibitor,TAI)和肿瘤血管靶向制剂(vascular targeting agent,VTA).TAI类旨在抑制肿瘤血管生成的过程,近年来研究较多的为血管内皮生长因子(VEGF)类、基质金属蛋白酶(MMP)类、血管抑素类、内皮抑素类等;而VAT类则是通过破坏肿瘤组织中已存在的血管从而使肿瘤坏死,主要包括小分子类VTA和生物类VTA.对近年来各类抗肿瘤血管治疗新药的种类、作用机制及各自的临床研究进展进行综述.     

几类重要的海洋抗肿瘤药物研究进展

目前对海洋抗肿瘤药物的研究已经成为全世界普遍关注的热点。近年来，苔藓抑素、ecteinascidin-743、海兔毒肽、膜海鞘素、psammaplin、软海绵素B等六类化合物的研究取得了较大进展。本文综述这几类海洋抗肿瘤药物及其衍生物的研究进展，并探讨海洋抗肿瘤药物发展的趋势。     

靶向抗肿瘤肽的构建及其生物学活性研究

目的构建重组靶向抗肿瘤肽(Citrostatin),研究其生物学活性。方法构建Citrostatin重组基因,经原核生物表达和纯化获得Citrostatin融合蛋白,通过内皮细胞杀伤实验、细胞毒活性实验、体外管状机构生成抑制实验等分析Citrostatin的生物学活性。结果Citrostatin融合蛋白经表达、酶切纯化后,目的蛋白纯度达90%以上。Citrostatin能明显抑制内皮细胞ECV304的增殖(IC50=2.28μmol/L),有效杀伤肿瘤细胞1990及NCI-H640(IC50分别为9.24,2.74μmol/L),并明显抑制体外管状结构的生成。结论成功构建了重组靶向抗肿瘤肽Citrostatin,细胞和血管水平研究表明该融合肽同时具有抑制肿瘤新生血管的形成和直接杀伤肿瘤的双重活性。     

从赤组织中分离到的福安肽的抗肿瘤活性的初步研究

目的研究从赤组织中分离到的福安肽(Fuantai,FAT)的抗肿瘤活性及对促血管生成因子表达的影响。方法MTT法检测FAT对体外培养的人癌细胞生长的影响;小鼠移植性肝癌(H22)模型用于检查FAT对肿瘤生长的影响;免疫组化法检查福安肽对癌组织促血管生成因子表达的影响。结果FAT对体外培养的人早幼粒白血病细胞(HL-60)、人子宫颈癌细胞(HeLa)和人低分化鼻咽癌细胞(CNE-2Z)的生长无明显影响;FAT无论腹腔注射还是灌胃都显著抑制小鼠移植性肝癌的生长,且对小鼠体重增长无明显影响。当FAT的用量为50.0 mg/(kg.d)(ip或ig)共21 d对H22的抑制率分别为67.5%和84.0%。免疫组化检测结果显示,FAT明显下调小鼠肝癌组织血管内皮细胞生长因子,碱性成纤维细胞因子和血小板衍生生长因子的表达。结论FAT的抗肿瘤活性可能与其抑制肿瘤血管生成有关。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.