肿瘤血管生成与肿瘤血管抑制治疗

1 肿瘤的血管依赖性 1.1 肿瘤生长的血管依赖性实体瘤的血管特性与正常组织有很大差异,首先肿瘤的生长依赖于血管生成,其次与正常组织有序的血管相比,肿瘤毛细血管环的形态大小异常,通透性较高,易于纤溶酶原和纤维从血管中渗漏和激活组织因子,从而形成高度聚集的血管外纤维沉淀,血流缓慢。无血管的原发肿瘤在早期通过组织间液获取从毛细血管渗透的营养物质,排泄代谢产物,并进行氧气交换。由于细胞增殖缓慢且数目有限,局部组织间液足以支持肿瘤细胞的生长,肿瘤的体积几乎不超过1mm~3～2mm~3,这种状态可维持相当长的时间,称为血管前期。随着肿瘤细胞的不断增殖,渗透过程已不能满足细胞生长的需要,瘤体的微环境改变,刺激肿瘤细胞和宿主细胞产生血管生长刺激因子,并下调血管生长抑制因子的产     

血管内皮细胞特异性受体在肿瘤血管靶向治疗中的应用

目前已发现的内皮细胞特异性酪氨酸激酶受体家族主要有两种:一种是VEGF受体家族,包括Flt-1(VEGFR-1),Flk-1/KDR(VEGFR-2)和Flt-4(VEGFR-3);另一种是Tie家族,包括Tie-1和Tie-2(Tek)。它们都具有信号传导所必需的酪氨酸激酶活性,在生理及病理性血管再生中发挥着关键性作用。近来以VEGF受体及Tie受体作为靶点的肿瘤血管靶向治疗报道日渐增多,现综述如下: 1 VEGF受体血管内皮细胞生长因子(VEGF)是一种内皮细胞特异性的丝裂源,能在体内诱导血管生成,是作用最强的血管形成因子之一,它的高亲和力结合位点仅位于血管内皮细胞上的3种VEGF受体,即Flt-1,Flk-1/KDR和Flt-4,这3种受体主要分     

血管生成抑制剂TNP-470与细胞毒药物Gemcitabine的抗胰腺癌生长和转移作用的比较研究

目的探讨血管生成抑制剂(TNP-470)和细胞毒药物(Gemcitabine)对胰腺癌裸鼠原位移植模型(SOI)生长、转移的抑制作用及其作用机制.方法把胰腺癌细胞株SW1990皮下种植生长的癌组织移植于裸鼠胰腺尾部,制备胰腺癌SOI模型;24只SOI模型随机分为TNP组(TNP-470 30 mg/kg,皮下注射,隔日一次,疗程8周)、GEM组(Gemcitabine 100 mg/kg,腹腔内注射,术后第0、3、6、9天给药)和对照组,术后第10周处死裸鼠.结果Gemcitabine侧重于抗胰腺癌生长,TNP-470则侧重抑制胰腺癌转移,两者均无显著的预后改善作用;TNP组的微血管密度(MVD)显著低于GEM组和对照组,GEM组的肿瘤增殖指数(PI)显著低于TNP组和对照组(均P＜0.05).结论血管生成抑制剂和细胞毒药物在抗肿瘤生长和转移的侧重点和作用机制方面均存在显著差异.     

消化道肿瘤抗血管生成治疗的临床研究进展

消化道肿瘤的生长，转移与复发是血管生成依赖的，故以肿瘤血管生成的各个环节及其发生过程中的生化改变为靶点，研制血管生成的抑制剂，可使肿瘤处于休眠状态，有效地抑制肿瘤生长，侵袭，转移和复发，将成为肿瘤防治的一条新途径。本文主要综述消化道肿瘤抗血管生成治疗的临床试验研究进展。     

肿瘤血管生成及其抗血管生成治疗的研究进展

肿瘤的生长和转移依赖于新生血管形成,血管内皮生长因子及其受体是目前发现的最重要的促肿瘤血管生长因子,在肿瘤血管生成过程中发挥关键作用。鉴于肿瘤血管生成在肿瘤生长、浸润和转移中的重要作用,近年来开始了抗血管生成治疗肿瘤的新方法——抗血管生成疗法。本文着重综述了肿瘤血管生成及其抗肿瘤血管生成治疗的研究进展。     

西咪替丁的抗消化道肿瘤作用

西咪替丁的抗消化道肿瘤作用诸琦史峰徐家裕吴云林ＳｕｂｊｅｃｔｈｅａｄｉｎｇｓＣｉｍｅｔｉｄｉｎｅ／ｐｈａｒｍａｃｏｌｏｇｙ；ｄｉｇｅｓｔｉｖｅｓｙｓｔｅｍｎｅｏｐｌａｓｍｓ／ｄｒｕｇｔｈｅｒａｐｙ；ｓｔｏｍａｃｈｎｅｏｐｌａｓｍｓ／ｄｒｕｇｔｈｅｒ...     

论消化道肿瘤中医药之防治

目的消化道肿瘤应用中医药整体疗法之优势和特色.消化道肿瘤呈上升趋势,其手术、化疗、放疗这三种疗法,虽是当今普遍采用的治疗消化道肿瘤的主要手段,但有一定弊端和局限性.为此,应把辨证的宏观的思维方法同机械的微观的思维方法有机结合起来,改变其片面认识,充分发挥中医药防治消化道肿瘤的优势和特色.所以将消化道肿瘤的发病分为始发期(早、中、晚),启动期(早、中、晚)、演变期、进展期,则有利于防治.在其治疗方面应把中医药标本兼治的整体疗法同心理疗法,药膳、饮食营养疗法有机结合起来.方法与结果50例食管癌患者服用李氏胃宝灵7号(由黄芪、代赭石、浙贝、壁虎等50多种纯中药组成),经系统全面跟踪追访观察,其中男39例,女11例,年龄48岁～80岁,平均58岁,均以内镜结合病理检查确诊50例全属中晚期.依据临床症状及病理分为轻度8例,中度33例,重度9例.经病检鳞状细胞癌46例,腺癌3例,未分化癌1例.咽下困难者采用夜间子时(2300～0100)服用药物或进食(此法系古代中医先辈经验).一般服用4～8疗程,缓解临床症状的有效率为88%,痊愈0例;显效12例,占24%;有效32例,占64%;无效6例,占l2%.存活5a以上者12例,占24%,存活1a～5a者29例,占58%,存活1a以下者9例,占18%,用李氏胃宝灵7号治疗食管癌有一定的远期疗效(P<0.05).50例胃癌患者均服用李氏胃宝灵8号(由党参、白术,枳实,檀香,佛手等40多种纯中药组成),均经过完整系统地跟踪追访观察,其中男37例,女13例,年龄43岁～78岁,平均61岁,50例病情全属进展期.根据临床症状并结合病理,轻度10例,中度32例、重度8例.经病检其中腺癌34例,粘液癌9例、实质性癌7例,一般服用5～l0个疗程以上,其缓解临床症状的有效率为82%,痊愈0例,显效14例,占28%;有效27例,占54%;无效9例,占18%.存活5a以上者占22%;存活1a～5a者32例,占64%;存活1a以下者7例,占14%,用李氏胃宝灵8号治疗胃癌有较好的治疗效果(P<0.03)用李氏胃宝灵7号和8号标本兼治整体调节,治疗消化道肿瘤通过益气补血养阴之法,调节全身机体免疫功能;用健脾养胃之法增强消化系统整体康复功能而扶正治本;用软坚散结、消散痰瘀之法祛除癌瘤毒邪以治其标结论中医药防治消化道肿瘤有其独有的优势及广阔的前景.     

小鼠结肠癌中巨噬细胞金属弹力蛋白酶对血管抑素生成和肿瘤血管生长的影响

目的 在小鼠模型体内探讨巨噬细胞金属弹力蛋白酶(macrophage metalloelastase,MME)分解纤溶酶原生成有生物学功能的血管抑素的途径,及其对肿瘤生长和微血管密度(MVD)的抑制作用.方法 构建重组质粒pEGFP-C1-MME.给90只小鼠分别皮下接种稳定转染pEGFP-C1-MME(MME转染组)、空质粒pEGFP-C1(空质粒转染组)和未转染(未转染组)的CT-26细胞,每组30只.应用放射性碘标纤溶酶原及其示踪技术分析体内血管抑素的生成情况.结果 各组肿瘤标本进行SDS-PAGE电泳,在MME转染组电泳胶中,蛋白相对分子质量为35×103和38×103的区域放射性明显高于空质粒转染组和未转染组(P值均为0.00).Western印迹检测发现三组均检测出35×103和38×103片段表达,通过灰度扫描分析发现上述2个片断在MME转染组表达强度为9.32±1.52和5.61±2.24,明显高于空质粒组(2.47±0.23和0.67±0.12,P值均为0.00)和未转染组(1.21±0.69和0.86±0.44,P值均为0.00).MME转染组MVD平均值和血管内皮生长因子(VEGF)荧光表达强度均明显低于空质粒转染组和未转染组(P值均为0.00).MME转染组小鼠皮下种植瘤平均体积小于空质粒组和未转染组(P值均为0.00).结论 MME是与血管抑素生成密切相关的间质金属蛋白酶,同时具有抑制结肠肿瘤血管形成的作用.

Abstract：

Objective To determine the pathway of macrophage metalloelastase (MME)generate active angiostatin by decomposing plasminogen and its effect on inhibiting growth of tumor and microvessel density (MVD) in vivo in mouse models. Methods The recombined plasmid pEGFPC1-MME was constructed. Thirty mice were subcutaneously inoculated with CT-26 cells that were stably transfected with pEGFP-C1-MME (MME-transfected group), 30 with CT-26 cells transfected with empty vector pEGFP-C1 (vector-transfected group) and 30 with CT-26 cells (non-transfected group). Radioiodination and radioisotope tracer were used to explore the pathway of angiostatin generation in vivo. Results SDS-PAGE electrophoresis analysis revealed that, in the PAGE gel contained the protein with molecular weights of 35 000 and 38 000, radioactivity in MME-transfected group was significantly higher than vector-transfected and non-transfected groups (P = 0. 00).Western blotting analysis demonstrated two bands containing 35 000 and 38 000 fragments in three groups. Quantification of the protein signals by image analysis revealed that the levels of 35 000 and 38 000 fragments were obviously increased in MME-transfected group (9.32±1.52 and 5.61±2.24,respectively) than those in vector-transfected (2.47 ± 0.23 and 0. 67 ± 0. 12, respectively) and nontransfected (1.21±0. 69 and 0. 86 ± 0.44, respectively) groups (P= 0.00). The average value of MVD and fluorescent express of vascular endothelial growth factor (VEGF) were lower in MMEtransfected group when compared with those in vector-transfected and non-transfected groups (P =0.00). The average tumor size in MME-transfected group was small in comparison with vectortransfected and non-transfected groups (P= 0.00). Conclusions MME is demonstrated to be one of matrix metalloproteinase that closely related with angiostatin production and has inhibitory effect on tumor growth in tumor-bearing mice.     

胰腺癌血管内皮细胞生物学特性的实验研究

目的 研究胰腺癌血管内皮细胞的形态学特征、种属来源、遗传学特征、体外血管形成能力、增殖能力等生物学特征.方法 将人胰腺癌肿瘤细胞接种于裸鼠胰腺内,获取胰腺癌血管内皮细胞.体外培养胰腺癌血管内皮细胞,记录传代次数和传代速度,光学显微镜下观察每代细胞的形态学特征.用染色体核型分析技术研究胰腺癌血管内皮细胞的种属来源及遗传学特征,经小管形成实验观察胰腺癌血管内皮细胞的体外血管生成能力.以人脐静脉血管内皮细胞为对照,采用MTT比色法定量分析胰腺癌血管内皮细胞的体外增殖状况.对数据进行单因素方差分析及两两比较.结果 在适合的培养条件下,胰腺癌血管内皮细胞每2至3d传代1次,达融合状态时呈单层生长,呈现“铺路石”样特征.胰腺癌血管内皮细胞的种属类型为人,可见大量多倍体细胞、非整数倍染色体细胞、核内染色体缺失、错位及无法分析的片段.胰腺癌血管内皮细胞能在体外形成中空的管状结构.在体外培养48和72 h后,胰腺癌血管内皮细胞组的吸光度分别为0.581±0.014和1.082±0.033,显著高于人脐静脉血管内皮细胞组[0.379±0.038(t=8.720,P=0.001)和0.604±0.026(t=19.883,P＜0.01)].结论 胰腺癌血管内皮细胞的种属来源与人胰腺癌细胞相同,具有血管内皮细胞的典型形态特征和体外血管生成能力,具有遗传不稳定性和活跃的增殖能力.     

肺癌血管内皮生长因子表达及其与血管新生和肿瘤细胞增殖关系的研究

目的　探讨肺癌血管内皮生长因子（VEGF）的表达及其与血管新生、肿瘤细胞增殖的关系。方法　63例肺癌患者手术切除标本,应用免疫组织化学技术,抗VEGF165单克隆抗体（单抗）检测VEGF表达,抗CD34单抗测定肿瘤内微血管密度（iMVD）以反映血管新生,抗增殖细胞核抗原（PCNA）单抗测定肿瘤细胞增殖指数。结果　32例（50.8%）VEGF呈阳性表达,iMVD为4～138.7（M=36）/×400,PCNA为0～92%（M=25.03%）;VEGF评分为高级的肺癌组织iMVD高于VEGF为阴性和低级的肺癌组织（P＜0.01）,iMVD与VEGF表达呈正相关（r     

Antiangiogenic therapy for liver metastasis of gastrointestinal malignancies

In about half of the patients with gastrointestinal carcinomas, surgical excision of the primary tumor is not curative because metastasis has already occurred. Recent investigations of metastasis have shown that angiogenesis plays an important role in this process. In solid tumors angiogenesis occurs continuously to provide a blood supply for the proliferating cancer cells. As a new and potent method to control metastasis, antiangiogenic therapy has attracted considerable interest. This therapy inhibits angiogenesis, inducing a dormant state in which tumors cannot grow; the prognosis may thus be remarkably improved. Antiangiogenic agents show a characteristic antitumor effect which is different from that of chemotherapy. Based on our experimental in-vivo data, we conclude that antiangiogenic agents should not be used only for achieving tumor shrinkage, like chemotherapy. These agents should be used to control micrometastases, as the therapeutic effect on such metastasis is excellent. In addition, antiangiogenic agents may be valuable for long-term administration to maintain tumor dormancy, because drug resistance does not develop and these agents have a sustained effect. Combinations with conventional anti-cancer treatments such as chemotherapy, radiotherapy, immunotherapy, or surgery may also be valuable.     

Antiangiogenic gene therapy for cancer treatment

It is now well established that tumor growth and spread are angiogenesis-dependent processes. Therefore, inhibition of angiogenesis is likely to be an effective anticancer approach. A gene therapy-mediated approach to the delivery of antiangiogenic agents has several advantages, including the potential for sustained expression. However, several variables need to be considered when designing this approach. In addition to the choice of angiogenesis inhibitor, these approaches include the system for gene transfer and the target for gene delivery/site of inhibitor expression. This review summarizes the major alternatives within each of these categories and provides illustrative examples of their use in preclinical models.     

Antiangiogenic therapy combined with immune checkpoint blockade in renal cancer

Antiangiogenic therapy with vascular endothelial growth factor (VEGF) inhibitors is the current first-line treatment in metastatic renal cell carcinoma (mRCC). Immunotherapy with checkpoint inhibitor has been recently added to the armamentarium of mRCC treatment. These therapies are based on treatment with antibodies that block programmed cell death-1 (PD-1), programmed cell death ligand 1 (PD-L1) pathways, demonstrating impressive response rates and improved survival in several tumour types. So far, nivolumab is the only approved anti-PD-1 monoclonal antibody after VEGF therapy in mRCC. According to preclinical and clinical studies, combination therapies with VEGF- and checkpoint inhibitors have synergistic effect achieving improved response rates. However, toxicity in some combinations is high. In this article, we present a review of the ongoing trials with these drug combinations for RCC.     

Antiangiogenic therapy in leukemia

Angiogenesis is a fundamental element of the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the cancerous cells. Activation, migration, proliferation and differentiation of endothelial cells into mature blood vessels is driven by several cytokines and growth factors, known to be dysregulated in hematological malignancies. Thus, therapeutic interventions designed to eradicate the malignant clone should incorporate modulation of the angiogenic cascade. Antiangiogenic agents which target different components of the neovascularization process are being investigated in various solid tumors known to have increased vascularity. The role of angiogenesis in hematological malignancies, the rationale for the use of angiosuppressive therapy for these entities, and the status of novel antiangiogenic agents in clinical trials are discussed.     

消化系肿瘤的介入治疗

编者按 胃、结直肠癌、肝癌是我国常见的消化系统恶性肿瘤,约占整个消化系肿瘤的50%以上,严重影响患者的生存质量.如何进行早期诊断、治疗并提高患者的生存质量一直是临床医生研究的方向.近年来,随着内镜和放射介入技术的不断发展,介入治疗已经成为一个介入传统内科学和外科学之间的临床治疗体系,具有安全、简便、并发症小等优点.     

Antiangiogenic therapy in multiple myeloma

In the recent years, several pieces of evidence have pointed out that disease progression in multiple myeloma (MM) is characterized by an increased bone marrow neovascularization. Targeting the mechanisms that control angiogenesis could thus represent an innovative therapeutic approach to MM. Thalidomide, a glutamic acid derivative with sedative properties, is able to inhibit angiogenesis in murine models; this compound has recently demonstrated to be effective in relapsed/refractory MM, leading to a 30-40% response, coupled with mild systemic toxicity. Inhibition of angiogenesis is probably just one of the mechanisms by which thalidomide exerts its action in MM, as immunomodulation and inhibition of cytokine production by bone marrow stroma could also be involved. At present, several studies are ongoing, aiming at testing thalidomide-based drug combinations, mainly with dexamethasone, but also with conventional chemotherapy; the results that have been obtained so far show a synergistic effect of the drug combinations, with a response rate ranging from 50 to 70% in pretreated patients. There is now growing interest in novel compounds with potential antiangiogenic effects, among them a promising activity both in vitro and in animal models has been displayed by thalidomide analogs, inhibitors of vascular endothelial growth factor receptor-2 and endostatin.     

Endoscopic therapy of lower gastrointestinal cancer

Since the 1960's, endoscopy has revolutionised the practice of gastroenterology. Although initially diagnostic, endoscopy is now playing an increasingly therapeutic role. There are many reasons to believe that therapeutic endoscopy will shape the practice of gastroenterology further in the future. Only a few years ago we relied on low-resolution fibreoptic endoscopes. Nowadays even standard equipment allows the mucosa to be scrutinised in great detail. Dedicated training in endoscopy together with attention to quality indicators such as polyp detection and caecal intubation rates will ensure that fewer early gastrointestinal cancers are missed in the future. Open access endoscopy and screening programs are being introduced in many Western countries which will also lead to more lesions being detected in their early stages. This chapter discusses the main issues surrounding the endoscopic therapy of lower gastrointestinal cancers.     

Photoradiation therapy in early gastrointestinal cancer

Endoscopic photodynamic therapy has been used in the treatment of 19 cases of upper gastrointestinal cancer of which six were superficial esophageal and 13 were early gastric cancer. Six patients subsequently underwent surgical resection. Residual tumors were found in the resected specimens of one esophageal carcinoma and in the two early gastric carcinomas. Technical problems resulted in one failure. Follow-up ranged from 4 months to 3 years and 11 months with no tumor recurrence in either the operated or unoperated patients. Other delivery systems are currently under investigation.