血管新生的生物学：最重要的分子机制

已经确定了许多血管新生的诱导物,包括血管内皮生长因子家族、血管生成素、转化生长因子、血小板衍生生长因子、肿瘤坏死因子-α、白介素和成纤维细胞生长因子家族。较好理解血管新生的生物学,可揭示治疗若干与这些复杂过程有关的疾病的新靶标。不同血管新生抑制剂可能的用途,目前正在临床加紧研究。本文对介导血管新生的最重要分子机制作了总结。     

肿瘤血管生成抑制剂的研究进展

肿瘤生长转移具有血管依赖性,肿瘤血管生成抑制剂能破坏或抑制血管生成,有效的阻止肿瘤生长、转移和复发,是近年来肿瘤研究的新热点之一,也是肿瘤防治的一条新途径。本文对肿瘤血管生成抑制剂的种类、作用机制及临床研究的新进展做一综述。     

血管生成抑制剂研究的进展

血管生成是实体肿瘤细胞的生长和转移的必要条件,血管生成能够为肿瘤细胞提供更多的营养物质和氧气。阻止肿瘤血管网的形成能够使肿瘤变小,能够阻止肿瘤的转移。由于抗血管生成药物具有毒性低、不易产生获得性耐药的特点。因此,通过抑制血管生成来抑制肿瘤生长成为目前肿瘤治疗的策略之一。     

MMP-9表达与胃癌血管生成的关系及其临床意义

目的探讨基质金属蛋白酶-9(MMP-9)在胃癌组织中的表达与肿瘤血管生成的关系,及二者与胃癌侵袭转移、预后的意义。方法应用免疫组织化学SP法进行研究,检测20例正常胃黏膜、60例根治性切除胃癌组织中MMP-9表达和微血管密度(MVD)情况。结果(1)60例根治性切除胃癌中,MMP-9阳性率为75.0%,MVD值均明显高于正常胃黏膜(P<0.01);MMP-9表达与胃癌MVD密切相关(P<0.01);MMP-9阳性表达、MVD均与胃癌浸润深度、淋巴结转移、病理分期有关;单因素分析显示MMP-9表达和高MVD(≥23)均影响胃癌的生存期,但多因素分析示只有淋巴结转移和MVD是影响胃癌生存期的独立预后因素。结论MMP-9表达与胃癌血管生成关系密切,并与胃癌侵袭、转移密切相关。淋巴结转移、MVD是影响胃癌预后的独立因素;检测MMP-9表达及MVD对胃癌预后判断有一定价值。     

乳腺癌血管生成拟态及其与基质金属蛋白酶-2表达的相关性研究

目的 探讨乳腺癌中是否存在血管生成拟态(VM),并通过研究其与基质金属蛋白酶-2(MMP-2)表达的相关性,初步探讨VM形成的机制.方法 选取女性乳腺癌的石蜡标本共146例作为试验组,再选取20例女性乳腺的良性病变作为对照组,进行过碘酸雪夫氏反应以及CD34的双重染色,观察VM是否存在,再对VM阳性者和阴性者均进行MMP-2染色,比较二者相互关系.结果 VM的阳性表达与肿瘤大小、病理分级和淋巴结转移有关(P＜0.05).高分化和中低分化乳腺癌组织中VM的阳性率比较,差异有统计学意义(P＜0.05).在有淋巴结转移的乳腺癌组织中及无淋巴结转移的乳腺癌组织中VM的阳性率比较,差异有统计学意义(P＜0.05).MMP-2在乳腺癌组织中表达阳性率与乳腺良性病变比较,差异有统计学意义(P＜0.05).MMP-2在乳腺癌组织中的阳性表达率与病理学分级、淋巴结转移有关.高分化的乳腺癌组织MMP-2阳性率和中低分化乳腺癌组织比较,差异有统计学意义(P＜0.05).有淋巴结转移的乳腺癌组织MMP-2阳性率和无淋巴结转移的乳腺癌组织比较,差异有统计学意义(P＜0.05).MMP-2在VM阳性组中阳性表达率显著高于阴性组,二者在乳腺癌组织中的表达呈正相关性(r=0.550,P＜0.05).结论 乳腺癌是中存在VM的,MMP-2表达同VM具有相关性.     

力达霉素通过下调VEGF表达抑制斑马鱼胚胎血管生成

本研究采用斑马鱼胚胎模型研究力达霉素在整体动物水平对血管生成的影响。力达霉素处理胚胎后, 利用形态学观察、血管染色法、转基因斑马鱼检测其对胚胎血管生成影响, 以荧光定量PCR和蛋白免疫印迹法检测VEGF基因的表达情况。结果显示: 力达霉素处理后, 胚胎出现心包水肿、血流速度减缓等症状; 血管生长率降低, 肠下静脉生成受到抑制。荧光定量PCR和蛋白免疫印迹检测表明, 力达霉素对胚胎的VEGF mRNA表达水平没有影响, 但VEGF蛋白的表达受到显著抑制。研究结果表明, 力达霉素可以下调VEGF蛋白表达, 从而抑制斑马鱼胚胎血管生成。     

基质金属蛋白酶与角膜新生血管

基质金属蛋白酶（matrix metallproteinases，lVllVIPs）是一组由结缔组织细胞分泌的、参与细胞外基质（extracellular matrix，ECM）降解的Zn^2＋依赖性的蛋白酶家族。MMPs几乎能降解除多糖以外的全部ECM成分，参与结缔组织的降解与重建、炎症反应、肿瘤扩散转移和缺血缺氧损伤等。本文主要阐述基质金属蛋白酶与角膜新生血管（corneal neovascularization，CNV）的关系。     

肿瘤新生血管生成抑制剂的研究进展

肿瘤血管生成柳制剂一类能破坏或抑制血管生成,有效地阻止肿瘤生长和转移的药物。按作用机制可分为5大类：①抑制基底膜降解。②直接抑制内皮细胞增殖。③抑制血管生长因子活化。④抑制内皮细胞特异性整合素／生存信号。⑤其他非特异性作用机制的药物。本文主要简介正在进行临床试验的肿瘤血管生成抑制剂的最新研究进展。     

血管生成抑制中药及其研究概况

1肿瘤血管的生长过程 血管新生是指从已存在的血管中生成新的毛细血管的过程。新生的血管是由原血管床以“出芽”或“分叉”的方式产生，以毛细血管内皮细胞增生开始，至形成新的微血管告终。体内的大部分血管保持高度的稳定性。但是，肿瘤、风湿病、牛皮癣等疾病能够破坏上述稳定性。导致血管新生．这些疾病可称为“血管生成病”或“血管生成性疾病”。血管新生抑制剂是治疗上述疾病的理想药物。     

新的血管生成抑制肽抗肿瘤血管生成的实验研究

目的观察一种新的血管生成抑制肽对肿瘤的抑制作用，并初步探讨作用机制。方法体外药效实验，采用MTT法及血管内皮细胞迁移法，体内采用Lewis肺癌瘤株皮下接种C57BL／6N小鼠，兔眼角膜烧伤模型。观察血管生成情况。结果新的血管生成抑制肽对血管内皮细胞增殖、迁移有明显的抑制作用。体内使Lewis肺癌皮下移植瘤体积明显缩小，并对烧伤诱导的兔眼角膜新生血管也具有明显抑制作用。结论新的血管生成抑制肽能明显抑制Lewis的肿瘤生长，其机制可能与抑制肿瘤血管生成有关。     

内皮抑制素通过抑制基质金属蛋白酶-2而抑制血管新生(英文)

目的　研究内皮抑制素抑制血管新生作用的机制。方法　用碱性成纤维细胞生长因子 (bFGF)处理体外原代培养人脐静脉内皮细胞 ;用三维胶原模型研究bFGF诱导的血管新生作用 ;用明胶电泳和蛋白印迹法研究分泌于培养基中的基质金属蛋白酶的活性和含量 ;RT PCR法研究基质金属蛋白酶的mRNA水平。结果　内皮抑制素显著抑制bFGF诱导的内皮细胞血管新生能力 ;抑制内皮细胞分泌的基质金属蛋白酶 2的表达及其mRNA的水平。结论　内皮抑制素通过抑制基质金属蛋白酶 2的表达而抑制血管新生     

Acetazolamide inhibits aquaporin-1 protein expression and angiogenesis

INTRODUCTION Recently the medical remedy for malignant tumorhas been concentrated to cut off the tumor nutritionsupply such as inhibiting the angiogenesis and otheraspects[1]. Angiogenesis, the formation of new bloodvessels, is essential for tumor progression and meta-stasis. Vigorous neovascularization, or angiogenesis,has been associated with a poor prognosis for cancersarising at several primary sites[2]. The process of an-giogenesis is required for sustaining tumor growth inthe …     

Cannabidiol inhibits angiogenesis by multiple mechanisms

BACKGROUND AND PURPOSE

Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis.

EXPERIMENTAL APPROACH

Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability – through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis – and in vitro motility – both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice.

KEY RESULTS

CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules.

CONCLUSIONS AND IMPLICATIONS

This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy.     

Combination high-dose etoposide and vincristine infusion

Following the identification of a synergistic antitumor effect in a murine model, the combination of etoposide and vincristine has been explored in the clinic. Etoposide was given at 4 dose levels (250, 500, 750 or 1,000 mg/m²) with each dose given in 3 equal fractions daily for 3 days. The dose of vincristine was fixed (two 0.75 mg infusions over 22 hours each between doses of etoposide). A total of 26 patients were entered into study and 7, 11, 10 and 5 patients were treated at the 250, 500, 750, and 1,000 mg/m² dose levels, respectively. Myelosuppressioh was the principle side effect and Grade 4 WBC toxicity (<>³) developed in 14%, 27%, 40% and 40%, respectively, of the patients treated at each of these respective dose levels. Life-threatening infections occurred in 0%, 9%, 30% and 60% of the patients at these levels, respectively. Reversal of marrow toxicity was rapid with repeat courses given at 3-week intervals. Non-hematologic toxicity, including neurotoxicity, nausea, vomiting, and mucositis was generally mild when present. Objective responses were observed in 1 patient each with refractory Hodgkin's disease and immunoblastic lymphoma. Prolonged periods of stable disease occurred in 2 patients with adenocarcinoma of the lung and one patient with Hodgkin's disease. The starting dose of etoposide recommended for further trials of this agent in combination with infusion of vincristine is 500 mg/m² given in fractionated doses; dose escalation should be possible in many patients.     

Acute encephalopathy associated with continuous vincristine sulfate combination therapy: case report

Summary Neurotoxicity is a well-recognized and commonly observed side effect associated with the use of vincristine sulfate in cancer chemotherapy. The clinical manifestations of vincristine neuropathy cover a wide spectrum of peripheral neurologic dysfunctions that have been described to be reversible and cumulative in most instances (1, 2). Paresthesias, loss of tendon reflexes, and progressive weakness are the most common clinical features (3, 4). Sensory impairment, cranial nerve palsies, gastrointestinal disturbances, and autonomie dysfunctions including atonic bladder, impotence, and orthostatic hypotension may occur (5). Acute CNS complications, usually presenting as generalized seizures, are extremely rare and only a few cases have been reported which were without underlying biochemical or structural abnormalities (1, 5–9). We describe the case of a woman with multiple myeloma, who developed fulminant encephalopathy following 4 days of continuous vincristine, adriamycin, and day 1–4 pulse dexamethasone (VAD) combination therapy.     

Antitubulin activity of vinblastine and vincristine

Summary The antitubulin activity of vinblastine and vincristine was compared by means of the radial segmentation test. Vinblastine was found to have antitubulin activity at least 6 times higher than that of vincristine. It is concluded that, if the differential indications for vinblastine or vincristine are balanced, it may be decisive for clinical treatment that more antitubulin activity can be administered as vinblastine than as vincristine.     

Oroxylin A,a classical natural product,shows a novel inhibitory effect on angiogenesis induced by lipopolysaccharide

BackgroundThere is an obvious relationship among angiogenesis and inflammation. From previous study, we learn that oroxylin A possesses anti-angiogenic activity in vitro and in ovo. It also has an inhibitory effect on inflammation. But whether oroxylin A suppresses the inflammation-induced angiogenesis is still unknown. Our present study focuses on the role of oroxylin A in targeting LPS-induced angiogenesis, inflammatory and related pathways.MethodsThe effects of oroxylin A on angiogenesis were investigated by transwell assay, tube formation assay, rat aortic ring assay and chorioallantoic membrane (CAM) model. Western blotting analysis was used to detect the expression of certain proteins.ResultsWe found that oroxylin A inhibited LPS-induced migration and tube formation of human umbilical vein endothelial cells (HUVECs), as well as microvessel sprouting from rat aotric ring in vitro and the angiogenesis of chicken chorioallantoic membrane (CAM) model in ovo. The results also indicated that oroxylin A could inhibit the expression of LPS acceptor toll-like receptor 4 (TLR4) and the activities of its downstream mitogen-activated protein kinases (MAPKs), including reducing expressions of the phosphorylation of JNK, p38, and ERK. Moreover, oroxylin A prevented NF-κB dimers from translocating to the nucleus.ConclusionsTaken together, oroxylin A can suppress the angiogenesis induced by LPS and it may affect the LPS/TLR4 signaling pathway.     

Synthesis and Evaluation of Noviose Replacements on Novobiocin that Manifest Anti-proliferative Activity

Structural modifications to the coumarin core and benzamide side chain of novobiocin have successfully transformed the natural product from a selective DNA gyrase inhibitor into a potent inhibitor of the Hsp90 C-terminus. However, no SAR studies have been conducted on the noviose appendage, which represents the rate-limiting synthon in the preparation of analogues. Therefore, a series of sugar mimics and non-sugar derivatives were synthesized and evaluated to identify simplified compounds that exhibit Hsp90 inhibition. Evaluation against two breast cancer cell lines demonstrated that replacement of the stereochemical complex noviose with simplified alkyl amines increased anti-proliferative activity, resulting in novobiocin analogues that manifest IC(50) values in the mid nanomolar range.