唑来膦酸在乳腺癌中抗肿瘤作用的研究现状

唑来膦酸作为第3代双膦酸盐药物已广泛用于乳腺癌骨转移相关事件的防治。唑来膦酸在乳腺癌中具有抗肿瘤治疗作用。唑来膦酸通过抑制乳腺癌细胞的增殖和诱导细胞凋亡,降低肿瘤细胞的迁移、侵袭能力,防止有利于肿瘤生长的骨微环境的形成,抑制肿瘤新生血管形成,调节免疫等多种途径直接或间接发挥其抗肿瘤作用,与放化疗及内分泌等辅助治疗有序贯协同增效作用。唑来膦酸在乳腺癌患者辅助治疗中的协同抗肿瘤作用也在几项相关的前瞻性临床试验中进行。     

唑来膦酸预防肿瘤骨转移的研究进展

骨转移导致的骨相关事件使患者生存时间缩短,生活质量下降,同时也增加了患者家庭的经济负担。研究表明,第三代双膦酸盐（Bisphosphonate,BPs）唑来膦酸（Zoledronic acid,ZOL）在治疗多种实体瘤骨转移骨相关事件以及延缓骨相关事件的发生方面有效。目前大量临床前及临床研究提示：ZOL 可能具有预防骨转移的作用。其机制可能涉及阻滞肿瘤细胞周期、诱导肿瘤细胞凋亡、抑制肿瘤细胞侵袭和肿瘤血管生成。因此,ZOL 可能对没有发生骨转移的早期癌症患者有预防骨转移的作用。本文就唑来膦酸预防骨转移的最新研究进展做一综述。     

唑来膦酸联合靶向及免疫调节药物的抗肿瘤研究进展

唑来膦酸是第三代含氮双磷酸盐,在临床中广泛用于治疗骨疾病。既往研究发现唑来膦酸在体内外对多种肿瘤细胞均有抗肿瘤作用,同时可以协同增加化疗、内分泌治疗、放疗等抗肿瘤疗效。最近研究发现,唑来膦酸亦可以协同增加靶向及免疫调节药物的抗肿瘤疗效,其抗肿瘤作用机制与抑制甲羟戊酸代谢途径、影响肿瘤信号通路、调节免疫反应、抗血管生成等有关。本文综述了唑来膦酸联合靶向及免疫调节药物在抗肿瘤治疗方面的研究进展。     

唑来膦酸在乳腺癌辅助治疗中的作用及其机制

双膦酸盐是治疗恶性肿瘤骨转移的有效药物之一,其作用机制是抑制破骨细胞介导的骨质重吸收.最新研究发现,新一代的双膦酸盐唑来膦酸可以诱导肿瘤细胞凋亡和抑制肿瘤血管新生,从而发挥直接或间接的抗肿瘤作用.有研究发现,对乳腺癌采用常用化疗药物序贯唑来膦酸治疗,可发挥协同抗肿瘤效应.唑来膦酸-弗隆辅助协同试验(Zometa-Femara Adjuvant Synergy Trial, ZO-FAST)和奥地利乳腺癌和结直肠癌研究小组-12(Austrian Breast and Colorectal Cancer Study Group-12, ABCSG-12)的最新研究结果显示,唑来膦酸在辅助治疗中与内分泌药物联用可显著提高患者的无病生存率和总生存率,而与辅助化疗联合使用的效果还有待唑来膦酸联合新辅助化疗降低复发(Neo-Adjuvant Zoledronic Acid to Reduce Recurrence,AZURE)临床试验予以证实.这些结果均表明,唑来膦酸用于乳腺癌的辅助治疗可以降低肿瘤的复发和转移.对唑来膦酸的最佳剂量和疗程尚有待进一步的研究予以确认.     

20（S）-人参皂苷Rg3对血管内皮细胞增殖和迁移的抑制作用

 目的 探讨20（S）-人参皂苷Rg3（SPG-Rg3）抗肿瘤诱导新生血管生成的作用机制。方法 采用MTT法、PCNA免疫荧光染色和Boyden小室迁移实验,观察SPG-Rg3对B16黑色素瘤细胞条件培养液（Conditioned Medium of B16 Melanoma Cells, BMCM）诱导的人脐静脉内皮细胞增殖和迁移的影响;并通过免疫细胞化学染色法观察了SPG-Rg3对B16黑色素瘤细胞血管内皮细胞生长因子（Vascular Endothelial Growth Factor, VEGF）及金属基质蛋白酶-9（Matrix Metalloproteinase-9, MMP-9）表达的影响。结果SPG-Rg3组BMCM的促内皮细胞增殖和迁移作用均明显弱于对照组,且SPG-Rg3浓度为5μg/ml时能够降低B16黑色素瘤细胞VEGF及MMP-9的表达。结论SPG-Rg3通过减少肿瘤细胞分泌细胞因子VEGF和MMP-9,抑制肿瘤细胞对血管内皮细胞增殖和迁移的促进作用,从而间接发挥其抗肿瘤新生血管生成的作用。     

双膦酸盐抗血管形成机制研究进展

双膦酸盐具有直接抗肿瘤和抗血管形成作用,具体机制仍未肯定.现有研究认为双膦酸盐通过干扰甲羟戊酸信号通路的关键激酶,使小G蛋白异戊酸化受阻等机制抑制内皮祖细胞分化和小管样形成,阻止血管发生;抑制血管内皮细胞的增殖、黏附和迁移能力,干扰血管形成;调节肿瘤血管形成细胞因子分泌,抑制血管形成相关基因等功能发挥其抗血管形成作用.     

抗肿瘤血管生成药物及血管生成相关因子的研究进展北大核心CSCD

0引言 肿瘤血管生成这一概念是20世纪70年代由Folkmant提出,称为“血管生成开关”;当肿瘤体积达N2mm。时,肿瘤需要独立的血供,血管生成在维持肿瘤快速生长中起关键性作用[1]。肿瘤血管生成方式包括出芽式、套入式、血管生成拟态、马赛克血管等,其中出芽方式最早报道且适用于大多数肿瘤。该过程包括毛细血管基底膜降解,血管内皮细胞迁移、增殖、形成管状结构,基底膜形成以及血流贯通等诸多环节。该过程主要由血管调节因子（包括肿瘤血管生成因子和肿瘤血管生成抑制因子）起中心调控作用,肿瘤细胞、炎症细胞可分泌多种细胞因子和炎性因子,这些因子作用于肿瘤微环境中的基质细胞、纤维原细胞等,从而促进肿瘤血管或抑制肿瘤血管生成,当两者的平衡被打破,肿瘤血管生成因子占优势时,即发生肿瘤血管生成。     

内皮素-1与肿瘤血管生成的关系

内皮素-1是一种血管收缩因子，近期研究发现肿瘤细胞和血管内皮细胞可以分泌内皮素-1，促使这些细胞增殖、迁移，抑制其凋亡，并通过促进VEGF分泌，协同作用于肿瘤血管生成。因此，内皮素-1被认为是一种新型血管生长因子，抑制内皮素-1的治疗可以在抗肿瘤血管生成中发挥一定的作用。     

MiRNA在肿瘤血管生成中的研究进展

摘 要：肿瘤血管生成在肿瘤的生长和转移过程中发挥重要的作用。微小RNA（microRNA,miRNA）是一类内源性单链非编码RNA分子,通过转录后水平调控广泛参与肿瘤相关生物学过程。MiRNA通过调控促血管生成因子、血管生成抑制因子及血管生成相关信号通路来促进或抑制肿瘤血管生成,并介导肿瘤细胞和血管内皮细胞间细胞通讯。全文对miRNA在肿瘤血管生成中的调控作用进行总结,并对miRNA作为抗肿瘤血管生成新的治疗手段及抗血管生成治疗效果生物标志物的临床意义进行讨论。     

唑来膦酸抗肿瘤作用的研究进展

唑来膦酸作为第三代双膦酸盐药物已广泛用于恶性实体瘤骨转移相关事件的防治。进一步研究发现,唑来膦酸可通过抑制甲羟戊酸途径中焦磷酸合酶的活性,使异戊烯焦磷酸大量蓄积,同时异戊烯焦磷酸与细胞内一磷酸腺苷结合形成三磷酸腺苷分解类似物蓄积于细胞中,从而改变细胞周期蛋白和凋亡蛋白水平,抑制肿瘤细胞生长并促进其凋亡,具有一定的直接和/ 或间接抗肿瘤作用。有关肺癌、乳腺癌、前列腺癌及肝癌等前期临床试验提示唑来膦酸与细胞毒药物、内分泌药物及靶向药物联合具有一定程度的协同抗肿瘤作用,并且在抗肿瘤药物之后序贯应用效果更好。一些相关的临床试验正在进行中。      

唑来膦酸在乳腺癌中抗肿瘤作用的研究进展

唑来膦酸(ZOL)是第三代双膦酸盐类药物的典型代表,在已上市的双膦酸盐类药物中应用最广泛、综合疗效最好,现已作为乳腺癌骨转移的常规治疗药物.多项临床前研究及临床研究已证实,唑来膦酸对肿瘤细胞有直接或间接的抑制作用,联合其他辅助治疗(化疗和内分泌治疗)可发挥协同作用,对改善乳腺癌患者术后生存、抑制复发及转移具有重要作用,本文就上述研究进展作一综述.     

血管生成拟态与肝癌研究进展

血管生成拟态的机制主要涉及肿瘤细胞基因型的转变、肿瘤细胞与细胞外基质的相互作用、肿瘤细胞分子信号改变.近年来的一些研究表明,肝癌组织中血管生成拟态的存在可能与肝癌的侵袭转移潜能以及较差的临床预后有关.     

CD44 enhances tumor aggressiveness by promoting tumor cell plasticity

Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM⁺) and non-aggressive (VM⁻) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry.     

Bisphosphonates: preclinical review

Bisphosphonates effectively inhibit osteoclast-mediated bone resorption and are integral in the treatment of benign and malignant bone diseases. The evolution of bisphosphonates over the past 30 years has led to the development of nitrogen-containing bisphosphonates (N-BPs), which have a mechanism of action different from that of the nonnitrogen-containing bisphosphonates. Studies conducted over the past decade have elucidated the mechanism of action and pharmacologic properties of the N-BPs. N-BPs exert their effects on osteoclasts and tumor cells by inhibiting a key enzyme in the mevalonate pathway, farnesyl diphosphate synthase, thus preventing protein prenylation and activation of intracellular signaling proteins such as Ras. Recent evidence suggests that N-BPs also induce production of a unique adenosine triphosphate analogue (Apppi) that can directly induce apoptosis. Our increased understanding of the pharmacologic effects of bisphosphonates is shedding light on the mechanisms by which they exert antitumor effects. As a result of their biochemical effects on protein prenylation, N-BPs induce caspase-dependent apoptosis, inhibit matrix metalloproteinase activity, and downregulate alpha(v)beta(3) and alpha(v)beta(5) integrins. In addition, zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ and Basel, Switzerland) exerts synergistic antitumor activity when combined with other anticancer agents. Zoledronic acid also inhibits tumor cell adhesion to the extracellular matrix and invasion through Matrigel trade mark and has antiangiogenic activity. A growing body of evidence from animal models demonstrates that zoledronic acid and other bisphosphonates can reduce skeletal tumor burden and prevent metastasis to bone. Further studies are needed to fully elucidate these biochemical mechanisms and to determine if the antitumor potential of bisphosphonates translates to the clinical setting.     

双磷酸盐在乳腺癌临床应用研究中的新进展

双磷酸盐（bisphosphonates,BPs）抑制破骨细胞介导的骨破坏,治疗乳腺癌骨转移疗效确切,成为乳腺癌骨转移的标准治疗。但近来研究结果表明BPs具有直接和间接的抗瘤活性,这使得BPs可能用于乳腺癌辅助治疗预防转移。BPs抗瘤效应还可直接诱导凋亡和抑制肿瘤趋化、移动、粘附和侵袭机制,可抑制乳腺癌细胞粘附于骨基质,间接效应还包括抑制内皮细胞增殖、血管生成以及免疫调节功能。此外,含氮BPs还有与细胞毒性药物协同效应,这些实验的结果将有可能为BPs更广泛应于乳腺癌辅助治疗奠定基础。临床数据也证实BPs不仅可以治疗骨转移,而且可以减少乳腺癌术后骨转移和内脏转移的发生,提高总生存率。也有数据提示BPs与化疗有协同作用,甚至有研究认为BPs可降低乳腺癌发生的危险。但BPs的临床数据还较有限并且其抗瘤效果尚存争议。有几项前瞻性临床试验正在进行以验证新一代BPs唑来磷酸在乳腺癌的抗瘤活性。本文对目前BPs在乳腺癌中的应用研究进展做一综述。      

黑色素瘤组织内三种血液供应模式时间关系的初步探讨

目的：探讨血管生成拟态（VM）、马赛克血管和内皮依赖性血管三种血液供应模式在肿瘤生长过程中的时间延续性变化。方法：将B16黑色素瘤组织块接种到C57纯系小鼠鼠鼷部．待肿瘤大小约0．5mm左右时．连续处死小鼠，将瘤组织块制作成切片．在切片上进行三种血液供应模式的计数．初步判定三种血液供应模式的时间关系趋势，同时利用双重免疫组化染色和电镜技术进行形态学观察.结果：随着肿瘤体积的不断增大．VM数目不断减少．而内皮依赖性血管数目呈现出不断增加趋势，马赛克血管的数目多少无明显变化．肿瘤体识的大小与内皮依赖性血管数目呈高度正相关（γ=0．718，P=-0．009）而与VM成高度负相关（γ=0．77，P=0．003）免疫组化双染和电镜观察的结果显示马赛克血管的管壁同时由内皮细胞和肿瘤细胞构成.结论：VM是黑色素瘤生长的早期血液供应的主要形式后来VM逐渐被内皮细胞依赖性血管替代，马赛克血管可能是VM和内皮依赖性血管之间的一种过渡形式.     

Microcirculation patterns in different stages of melanoma growth

Several microcirculation patterns in tumors have been reported, including vasculogenic mimicry (VM), mosaic vessels (MV) and endothelium-dependent vessels. To investigate the sources of blood supply during different tumor stages, we studied the correlation between expression of vasculogenic mimicry (VM), mosaic vessels (MV) and endothelium-dependent vessels in a mouse melanoma xenograph. Sixty C57 mice were divided into 12 groups (5 mice per group) and inoculated with B16 melanoma cells. Eleven days later, the average tumor size was approximately 0.2 to 0.3 cm. From days 11 to 22, one group per day was randomly sacrificed, and the density of vasculogenic mimicry, mosaic vessels and endothelium-dependent vessels was measured in tumor tissue sections. Immunohistochemical dual-staining and electronic microscopy were also used to confirm the vessel types. All three types of microcirculation patterns were observed during tumor development. In the early stage of tumor growth, vasculogenic mimicry is the main pattern of blood supply. As the area of tumor tissue expands and the number of endothelium increase, vasculogenic mimicry is replaced by endothelium-dependent vessels. Mosaic vessels might be the interim state between vasculogenic mimicry and endothelium-dependent vessels. The number of endothelium-dependent vessels correlated with the size of the tumor (r=0.718, P=0.009), while the number of vasculogenic mimicry was inversely correlated (r=0.77, P=0.003). In conclusion, the number of vasculogenic mimicry decreased and the number of endothelial-dependent vessels increased during tumor growth.