内皮抑素概论及抗肺癌作用

肿瘤的生长转移与肿瘤血管生成密切相关,抗血管生成是治疗肿瘤的新策略.内皮抑素是特异性的血管内皮细胞生长抑制因子,能显著抑制肿瘤血管增生并诱导肿瘤细胞凋亡.内皮抑素的抗血管生成治疗和血管靶向基因治疗,为治疗肺癌提供了广阔前景 .     

肿瘤血管生成抑制剂

恶性肿瘤的发展与侵袭均依赖于新生血管生成。肿瘤新生血管的生成受多种调节因子作用,这些调控因子主要有：血管内皮生长因子、血管生成素,成纤维细胞生长因子,血管抑素,内皮抑素,thrombospondin(TSP-1)等。通过抑制肿瘤新生血管的生成可以阻止肿瘤的发展和转移,甚至使肿瘤消退。抗血管生成药物为肿瘤的治疗提供了一个全新的思路,本文简单讨论了肿瘤血管生成与调节机制并着重介绍肿瘤血管生成抑制剂的研究进展。     

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)、     

抑制肿瘤血管生成疗法的研究进展

简要回顾抗血管生成疗法在肿瘤治疗中的重要成果,着重概括抑制血管生成的四主要环节:中和血管形成促进物、使用血管形成抑制物、调节血管抑素和内皮抑素、靶向肿瘤内皮细胞,并列举了部分进入临床试用的抗血管药。在综述既往研究成果的基础上,提出抗肿瘤血管疗法的未来展望。     

抗肿瘤血管治疗的新进展

肿瘤的发生、生长和转移与肿瘤的新生血管的形成密切相关 ,调节肿瘤新生血管生成的因子主要有促进因子和抑制因子两大类。较为重要的促进因子有血管内皮细胞生长因子 (VEGF)、碱性成纤维细胞生长因子 (b FGF)、血管生成素 (angiopoi-etin)、整合素 (integrins)等 ,这些因子与受体结合发挥其促血管生成的作用 ,因此阻断这些因子和受体的结合以及受体后信号传导途径可以抑制血管的生成。较为重要的血管生成抑制因子有内皮抑素(endostatin)、血抑素 (angiostatin)、凝血酶敏感蛋白 (thrombospondin,TSP)、基质金属蛋白酶 (ma-trix metallop…     

肿瘤血管生成及其供血模式研究进展

在肿瘤的生长、侵袭和转移过程中,肿瘤血管生成研究尤为重要。本文对目前研究较多的肿瘤血管生成过程、相关影响因子及不同供血模式等方面做…综述。研究表明肿瘤生长分为无血管的缓慢生长阶段和血管快速增长阶段。在无血管的缓慢生长阶段,促血管生成因子（如血管内皮细胞生长因子VEGF、成纤维细胞生长因子FGF、整合素INT等）和血管生成抑制因子（如内皮抑素Es、血管抑素AS、血小板反应蛋白-1TSP-1等）处于平衡状态,当实体肿瘤达到或超过1-2mm2时,单纯依靠弥散作用已不能满足自身营养需求,肿瘤自身缺血缺氧诱导促血管生成因子产生,平衡状态被打破,血管生成表型启动。在肿瘤的生长过程中,各种因子相互作用,肿瘤组织内部会出现不同的供血模式,主要有血管生成拟态VM、马赛克血管MV和内皮依赖性血管三种。VM完全以肿瘤细胞变形构建：MV由不连续内皮细胞和肿瘤细胞相间构建;内皮依赖性血管完全由内皮细胞衬覆。有文献将此三种模式称为“三阶段现象”即肿瘤供血模式由Ⅷ到MV再到内皮依赖性血管。目前,抗血管生成在肿瘤治疗研究中占据重要的地位,但还有许多问题尚未清晰。我们更需进一步研究,为抗血管生成在临床上的应用及与传统抗肿瘤治疗方法的结合提供充实的理论依据。     

肿瘤血管生成的靶向调控及其药物研究进展

肿瘤血管生成(Tumor Angiogenesis)对大多数实体瘤的生长和转移具有重要意义,是多步骤多因素参与复杂的病理过程.选择肿瘤血管生成中的一些关键环节或参与的重要因子作为靶点,研制应用特异性肿瘤血管生成抑制剂或抗体,以靶向调控肿瘤血管生成,控制肿瘤的生长和转移,达到治疗肿瘤的目的.本文对近年来肿瘤血管生成机制和肿瘤血管生成抑制剂的研究进展进行综述.     

肿瘤抑素活性肽段及其衍生物研究新进展

肿瘤抑素(tumstatin)是继内皮抑素(endostatin)和血管生成抑素(angiostatin)发现以来,来源于人血管基膜Ⅳ型胶原蛋白的极具潜力的肿瘤抑制因子。它强大的抗肿瘤新生血管生成、诱导肿瘤细胞和内皮细胞凋亡等生物活性,使其成为近年来的研究热点。本文详细介绍了肿瘤抑素活性肽段及其衍生物的研究进展。对Tum-5、T7肽和19肽以及这些活性肽段连接NGR导向肽或人源性IgG3铰链区等肽段后形成的衍生物作了较详细的介绍。肿瘤抑素的活性肽段及其衍生物,以高选择性、高活性、低毒性等优点正成为抗肿瘤药物研究的新希望。     

内皮抑素临床研究新进展

早在20世纪初,Goldman就观察到血管围绕肿瘤生成现象。1971年,Judah Folkman博士提出“肿瘤生长和转移依赖血管生成,阻断血管生成是遏制肿瘤生长的有效策略”,即所谓的肿瘤饥饿疗法。其中,1997年发现的内皮抑素(Endostatin)[1]因抑制血管生成作用强而备受关注。本文就内皮抑素临床应用的最新进展作一综述。1生物学特性及作用机制1·1起源和结构特征1997年,O'Reilly MS等[1]发现,可从体外培养的小鼠血管内皮细胞瘤(EOMA)的细胞培养液中提纯出内皮抑素,且与人的内皮抑素同源性极高。经氨基酸序列分析表明,二者大约有86%完全一致,仅人的内…     

肿瘤血管靶向剂的研究进展

近年来有人认为血管靶向疗法的用药应被分为抗血管生成药和血管分裂剂(vascular disrupt agents,VDA),认为先前的VTA其实应是VDA,这一观点正在得到越来越多的认同。这个观点认为两者在生理靶标,敏感疾病的类型和范围以及治疗方案三个方面存在差异。众所周知,快速增殖的肿瘤血管     

不同频率电刺激VTA对吗啡成瘾大鼠ACbSh的放电活动的影响

目的:观察电刺激大鼠腹侧被盖区(VTA)对吗啡成瘾大鼠伏隔核壳部(ACbSh)神经元的影响,为应用脑深部电刺激技术治疗阿片类药物成瘾提供实验依据。方法:采用单管玻璃微电极细胞外记录法,观察不同频率电刺激VTA对吗啡成瘾大鼠ACbSh神经元放电的影响。结果:低频(50Hz)电刺激VTA,吗啡组ACbSh神经元主要表现为无反应(47.83%);高频(135Hz)电刺激VTA,吗啡组多数ACbSh神经元表现为抑制性作用(50.00%)。结论:高频电刺激VTA有可能作为新方法用于治疗阿片类药物成瘾。     

以血管内皮生长因子及其受体为靶点的肿瘤血管生成抑制剂的研究进展

肿瘤的生长和转移依赖于新生血管的形成,血管内皮生长因子(VEGF)在肿瘤新生血管形成中起关键作用。以VEGF及其受体为靶点,通过抑制肿瘤血管生长,从而遏制肿瘤的生长和转移的研究已经取得了一定的成果,在此对肿瘤血管生成抑制剂(TAI)的研究进展进行综述。     

Combretastatin A4的抗肿瘤作用研究进展*

肿瘤细胞的生存和发展需要完整的血管系统提供氧气、养料并输送废物,同时提供转移的主要路线,因此肿瘤血管成为肿瘤治疗中一个很有吸引力的靶点。以往大量的研究集中在抗新生血管生成方面,近年来对于肿瘤血管靶向药物(Vascular targeting agents)的研究逐渐增多,此类药物针对肿瘤既存血管产生迅速且有选择性的破坏作用,使肿瘤细胞由于氧气和养料缺乏而死亡。Combretastatin A4作为其中的一个候选化合物,吸引众多的研究人员对其体内外药理作用进行研究,该候选化合物的水溶性前药已经被OxiGen公司开发,目前在美国和欧洲进行II期临床试验,且已获准进入美国FDA快速通道审批。现就其体内外药效学、作用机制以及临床研究进展作一综述。     

Lesion of medial prefrontal cortex reduces morphine-induced extracellular dopamine level in the ventral tegmental area: a microdialysis study in rats

Drug addiction is a chronic disorder characterized by compulsive drug-seeking behavior despite severe negative consequences. Most abused drugs increase dopamine release in the ventral tegmental area (VTA) and in the nucleus accumbens (NA). The medial prefrontal cortex (mPFC), a part of the mesocorticolimbic dopaminergic system, receives dopaminergic projections from VTA; and in turn, sends glutamatergic projections to both VTA and NA. The present study was designed to further investigate the involvement of the mPFC in the release of dopamine in the VTA by using in vivo microdialysis and high performance liquid chromatography with electrochemical detection (HPLC-ECD). Electrical lesion of the mPFC decreased the level of dopamine in the VTA to approximately 26.8% of basal level. Acute morphine (40 mg/kg i.p.) treatment increased the level of dopamine in the VTA, while the lesion of mPFC immediately before morphine administration attenuated the effects of acute morphine on the level of dopamine. These results suggest that the mPFC modulates dopamine release into the VTA.     

钙调神经磷酸酶在大鼠甲基苯丙胺诱导的行为敏化中的作用

目的:钙调神经磷酸酶是一种丝氨酸/苏氨酸磷酸酶,此磷酸酶被激活后可去磷酸化许多底物蛋白,如钙通道、AMPA受体、NMDA受体、突触蛋白I、多巴胺和环磷酸腺苷调节磷蛋白32(DARPP32)以及环磷酸腺苷反应元件结合蛋白(CREB)等,通过调节这些目标靶蛋白而参与神经元突触可塑性的调节。反复给予精神兴奋剂能够导致动物自发活动逐渐增加的现象称为行为敏化,它是用以研究药物成瘾后反复、连续的强迫性用药行为的一种动物模型,能够为临床研究成瘾者强迫性用药以及复吸提供理论基础。本文目的在于研究钙调神经磷酸酶在大鼠甲基苯丙胺诱导的行为敏化中的作用。方法:1)系统给予钙调神经磷酸酶的抑制剂环孢素A,考察钙调神经磷酸酶在大鼠甲基苯丙胺行为敏化形成中的作用。SD大鼠分为四组:生理盐水+溶媒组,生理盐水+环孢素A组,甲基苯丙胺+溶媒组,甲基苯丙胺+环孢素A组,每日给予大鼠生理盐水/甲基苯丙胺(1mg·kg-1ip)注射,注射前90min给予环孢素A(15mg·kg-1,ip)溶媒处理,注射后立即进行2h自发活动的测定,连续14d。2)考察钙调神经磷酸酶的抑制剂对于甲基苯丙胺诱导的大鼠自发活动的影响。SD大鼠分为两组:生理盐水+溶媒组,生理盐水+环孢素A组,每日给予大鼠注射生理盐水(1mg·kg-1),注射前90min给予环孢素A(15mg·kg-1,ip)/溶媒处理,注射后立即进行2h自发活动的测定,连续14d,考察系统给予环孢素A对于大鼠甲基苯丙胺诱导的行为敏化形成的影响。在d15进行甲基苯丙胺(1mg·kg-1)的challenge,考察环孢素A预处理之后,大鼠对甲基苯丙胺诱导的自发活动的影响。3)VTA微注射环孢素A,考察钙调磷酸酶对于大鼠甲基苯丙胺诱导的行为敏化的作用。SD大鼠分为四组:生理盐水+溶媒组,生理盐水+环孢素A组,甲基苯丙胺+溶媒组,甲基苯丙胺+环孢素A组,每日给予大鼠生理盐水/甲基苯丙胺(1mg·kg-1ip)注射,注射前90minVTA微注射环孢素A(1μg/侧)/溶媒(DMSO)处理(隔日微注射一次),注射后立即进行2h自发活动的测定,连续14d,考察VTA微注射环孢素A对大鼠甲基苯丙胺诱导的行为敏化形成的影响。4)VTA微注射环孢素A对于甲基苯丙胺诱导的大鼠自发活动的影响。SD大鼠分为两组:生理盐水+溶媒组,生理盐水+环孢素A组,每日给予大鼠注射生理盐水(1mg·kg-1),注射前90min VTA微注射环孢素A(15mg·kg-1,ip)/溶媒处理(隔日微注射一次),注射后立即进行2h自发活动的测定,连续14d。在d15进行甲基苯丙胺(1mg·kg-1)的challenge,考察VTA微注射环孢素A预处理之后对大鼠甲基苯丙胺诱导的自发活动的影响。结果:系统给予钙调磷酸酶的抑制剂环孢素A能够抑制大鼠甲基苯丙胺诱导的行为敏化的形成,环孢素A预处理对大鼠自发活动没有影响。d15给予甲基苯丙胺challenge能够显著增加大鼠自发活动,但环孢素A预处理对甲基苯丙胺急性处理诱导的大鼠自发活动增高没有影响。VTA微注射环孢素A亦能够抑制大鼠甲基苯丙胺诱导的行为敏化的形成,而VTA环孢素A预处理对于甲基苯丙胺急性处理诱导的大鼠自发活动增加亦没有影响。结论:钙调磷酸酶的激活,特别是在中脑腹侧被盖区(VTA),可能参与了大鼠甲基苯丙胺诱导的行为敏化过程,并且对突触可塑性的调节具有重要作用。     

小分子肿瘤血管破坏剂研究进展

 靶向肿瘤血管系统作为肿瘤治疗的策略已经取得了很好的临床疗效。目前上市的药物主要是抑制肿瘤的血管新生,而肿瘤血管具有的分级不规则、网络混乱等特点使得靶向既存的肿瘤血管成为可能。小分子肿瘤血管破坏剂是近年来出现的一类靶向既存血管系统的化合物,该类化合物可以快速、选择性地破坏既存的肿瘤血管网络从而引发肿瘤的坏死。目前已经有多种小分子肿瘤血管破坏剂进入临床前和临床评价,其显示的良好的体内外抗肿瘤效果为肿瘤的治疗提供了新的策略。文中综述小分子血管破坏剂的作用效果、作用机制和临床研究进展,深入理解其具体作用机制对于这类药物的开发具有重要的意义。     

Hyposensitivity to Gamma-Aminobutyric Acid in the Ventral Tegmental Area During Alcohol Withdrawal: Reversal by Histone Deacetylase Inhibitors

Putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons have an important role in alcohol addiction. Acute ethanol increases the activity of pDAergic neurons, and withdrawal from repeated ethanol administration produces a decreased sensitivity of pDAergic VTA neurons to GABA. Recent studies show that behavioral changes induced by chronic alcohol are reversed by inhibitors of histone deacetylases (HDACs). Whether HDAC-induced histone modifications regulate changes in GABA sensitivity of VTA pDAergic neurons during withdrawal is unknown. Here, we investigated modulation of withdrawal-induced changes in GABA sensitivity of pDAergic VTA neurons by HDAC inhibitors (HDACi), and also measured the levels of HDAC2, histone (H3-K9) acetylation, and GABA-Aα1 receptor (GABA (A-α1) R) subunit in VTA during ethanol withdrawal. Mice were injected intraperitoneally (ip) with either ethanol (3.5 g/kg) or saline twice daily for 3 weeks. In recordings from pDAergic VTA neurons in brain slices from ethanol-withdrawn mice, sensitivity to GABA (50–500 μM) was reduced. In brain slices from ethanol-withdrawn mice incubated with the HDACi SAHA (vorinostat) or trichostatin A (TSA) for 2 h, the hyposensitivity of pDAergic VTA neurons to GABA was significantly attenuated. There was no effect of TSA or SAHA on GABA sensitivity of pDAergic VTA neurons from saline-treated mice. In addition, ethanol withdrawal was associated with an increase in levels of HDAC2 and a decrease in histone (H3-K9) acetylation and levels of GABA (A-α1) R subunits in the VTA. Therefore, blockade of upregulation of HDAC2 by HDACi normalizes GABA hyposensitivity of pDAergic neurons developed during withdrawal after chronic ethanol treatment, which suggests the possibility that inhibition of HDACs can reverse ethanol-induced neuroadaptational changes in reward circuitry.     

血管内皮靶向性抗肿瘤多肽研究的新思路

概述近年来血管内皮靶向性抗肿瘤多肽研究状况，并提出研究的新思路，即针对两种重要的肿瘤血管内皮特异性分子标记——生长因子和整合索，设计开发作用于肿瘤血管内皮的抗肿瘤多肽，使该类药物研发由大规模筛选走向更具理性和靶向性。     

Functional selectivity and time-dependence of μ-opioid receptor desensitization at nerve terminals in the mouse ventral tegmental area

BACKGROUND AND PURPOSE

The majority of studies examining desensitization of the μ-opioid receptor (MOR) have examined those located at cell bodies. However, MORs are extensively expressed at nerve terminals throughout the mammalian nervous system. This study is designed to investigate agonist-induced MOR desensitization at nerve terminals in the mouse ventral tegmental area (VTA).

EXPERIMENTAL APPROACH

MOR function was measured in mature mouse brain slices containing the VTA using whole-cell patch-clamp electrophysiology. Presynaptic MOR function was isolated from postsynaptic function and the functional selectivity, time-dependence and mechanisms of agonist-induced MOR desensitization were examined.

KEY RESULTS

MORs located at GABAergic nerve terminals in the VTA were completely resistant to rapid desensitization induced by the high-efficacy agonists DAMGO and Met-enkephalin. MORs located postsynaptically on GABAergic cell bodies readily underwent rapid desensitization in response to DAMGO. However, after prolonged (>7 h) treatment with Met-enkephalin, profound homologous MOR desensitization was observed. Morphine could induce rapid MOR desensitization at nerve terminals when PKC was activated.

CONCLUSIONS AND IMPLICATIONS

Agonist-induced MOR desensitization in GABAergic neurons in the VTA is compartment-selective as well as agonist-selective. When MORs are located at cell bodies, higher-efficacy agonists induce greater levels of rapid desensitization than lower-efficacy agonists. However, the converse is true at nerve terminals where agonists that induce MOR desensitization via PKC are capable of rapid agonist-induced desensitization while higher-efficacy agonists are not. MOR desensitization induced by higher-efficacy agonists at nerve terminals only takes place after prolonged receptor activation.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Motor stimulant effects of ethanol and acetaldehyde injected into the posterior ventral tegmental area of rats: role of opioid receptors

Rationale  A recently published study has shown that microinjections of ethanol, or its metabolite, acetaldehyde into the substantia nigra pars reticulata, are able to produce behavioral activation in rats. Another brain site that could participate in such effects is the ventral tegmental area (VTA). Objectives  We have investigated the locomotor-activating effects of local microinjections of ethanol and acetaldehyde into the posterior VTA of rats and the role of opioid receptors in such effects. Materials  Cannulae were placed into the posterior VTA to perform microinjections of ethanol (75 or 150 nmol) or acetaldehyde (25 or 250 nmol) in animals not previously microinjected or microinjected with either the nonselective opioid antagonist naltrexone (13.2 nmol) or the irreversible antagonist of the μ-opioid receptors β-funaltrexamine (β-FNA; 2.5 nmol). After injections, spontaneous activity was monitored for 60 min. Results  Injections of ethanol or acetaldehyde into the VTA increased the locomotor activity of rats with maximal effects at doses of 150 nmol for ethanol and 250 nmol for acetaldehyde. These locomotor-activating effects were reduced by previously administering naltrexone (13.2 nmol) or β-FNA (2.5 nmol) into the VTA. Conclusions  The posterior VTA is another brain region involved in the locomotor activation after the intracerebroventricular administration of ethanol or acetaldehyde. Our data indicate that opioid receptors, particularly the μ-opioid receptors, could be the target of the actions of these compounds in the VTA. These results are consistent with the hypothesis that acetaldehyde could be a mediator of some ethanol effects.