低氧诱导因子-1α对细胞信号、细胞凋亡的影响及研究进展

低氧诱导因子-1（hypoxia—induciblefactor-1，HIF-1）是普遍存在于人和哺乳动物细胞内的缺氧应答调控因子，通过调控一系列与缺氧适应有关基因的表达以保持机体的氧稳态。HIF-1（尤其是HIF-1α）的表达水平与糖酵解、细胞周期阻滞、细胞生存与增殖、血管新生、血管舒缩、红细胞生成、肿瘤生长和转移以及肿瘤多药耐药等许多生命活动密切相关。多数肿瘤具有缺氧的微环境。HIF-1α对于肿瘤的效应是多方面的：HIF-1α在上游调控诸多与肿瘤发生密切相关的基因；肿瘤在低氧条件下选择更恶性的表型；增加细胞突变率；增加与血管新生和肿瘤侵袭有关的基因表达；低氧条件下细胞更具有耐药倾向。因此HIF-1α已经成为一个治疗肿瘤的新的关键性靶点。细胞信号、细胞凋亡在多细胞生物的个体发育、自稳平衡等生理以及肿瘤、炎症等病理过程中具有重要意义，理解HIF-1α对于细胞信号、细胞凋亡的调节，对于开发特异性的肿瘤治疗有着现实意义。现就HIF-1α对细胞信号、细胞凋亡的影响及研究进展作一综述。     

逆转录-多聚酶链式反应方法检测临床肝癌组织的多药耐药基因表达

化疗是治疗肿瘤的有效手段之一。肿瘤细胞耐药是导致化疗失败的主要原因,有关资料统计,90％以上肿瘤患者死因或多或少都与耐药有关。因此,研究肿瘤耐药起因、检测病人是否出现耐药,借以指导临床化疗,提高患者治愈率和生存率是当前肿瘤治疗迫切需要解决的重要课题。本实验采用逆转录-多聚酶链式反应(RT-PCR)技术建立了     

瘤内菌群与抗肿瘤药疗效关联度的研究进展

肿瘤耐药是临床肿瘤治疗面临的重要难题。除一些传统机制外,最新研究发现不同肿瘤内存在不同瘤内菌群,而这些细菌也可能通过不同机制介导肿瘤耐药。此外,瘤内菌群也可对目前的一些新兴疗法如免疫治疗、靶向治疗及中医药治疗产生影响。本综述简要介绍瘤内菌群的种类及特点,探讨瘤内菌群导致肿瘤耐药的机制,总结现有耐药药物,概述瘤内菌群与抗肿瘤药疗效的关联度,并展望通过影响瘤内菌群提高抗肿瘤药疗效的未来研究方向。     

小檗碱逆转肿瘤多药耐药的研究进展

肿瘤发病率高、死亡率高，预后差。化疗是肿瘤治疗的主要手段，而化疗耐药问题日益凸显，故寻找克服化疗耐药、提高治疗效果的方法成为亟待解决的问题。当前，随着研究的发展，一些中药的抗肿瘤效果得到了广泛关注。临床上用于治疗消化系统疾病的小檗碱已被证明具有抗肿瘤以及逆转肿瘤多药耐药的作用。该文总结了近年来国内外有关小檗碱逆转肿瘤药物耐药的研究，以期探索其改善肿瘤耐药治疗效果和预后的手段。     

中药逆转肿瘤多药耐药的潜力

通过对中药抗肿瘤耐药性的研究进展的探讨,综述和分析肿瘤多药耐药发生机制与逆转的药物,并对比西药来分析中药逆转肿瘤多药耐药的特征及优势,表明中药的科学性、治疗有效性、抗肿瘤作用的开发潜力很大,提出了基础研究的方向与中药逆转多药耐药的临床应用潜力与前景。     

原发性肝细胞癌对索拉非尼耐药机制的研究进展

索拉非尼是目前公认的治疗晚期原发性肝细胞癌的分子靶向药物,但原发性肝细胞癌对其耐药性的出现,影响了药物对肝癌的疗效。原发性肝细胞癌对索拉非尼耐药存在多种机制。肝癌细胞本身表皮生长因子受体的表达上调及其下游信号通路的异常改变,沉默信息调节因子1的过表达,肝癌细胞的自噬能力增强及间充质转变均可能导致其对索拉非尼耐药。肝癌血管内皮细胞出现耐药,肿瘤微环境中缺氧诱导因子-1α、趋化因子及其受体上调等也可能影响肿瘤对索拉非尼的敏感性。该文就原发性肝细胞癌对索拉非尼耐药机制的研究进展进行综述。     

肿瘤干细胞的耐药性及其治疗策略

随着对肿瘤研究的不断深入,以及对干细胞了解的日益加深,越来越多的证据表明肿瘤中某些细胞具有干细胞特性,由此提出了肿瘤干细胞学说。这一学说,不仅认为肿瘤的生长、转移与肿瘤干细胞的关系密切,而且传统的化疗方法不能根治肿瘤的原因可能也与肿瘤干细胞耐药有关。已有研究表明, ABC转运体能够保护肿瘤干细胞免受药物的毒性作用,因此更深入的理解肿瘤干细胞耐药机制对我们找到行之有效的肿瘤治疗方法以及新的治疗靶点有十分重要的意义。     

以bcl—2基因为靶标的反义治疗克服肿瘤化疗耐药

化疗耐药是肿瘤治疗中的难题,研究耐药机制和寻求克服途径成为当今肿瘤防治的重点。ｂｃｌ－２是一个重要的细胞凋亡抑制基因,在许多肿瘤上超量表达。临床和分子生物学证明,ｂｃｌ－２超量表达与化疗耐药有关。应用反度药物抑制ｂｃｌ－２基因表达,肿瘤细胞能恢复对化疗药物治疗的敏感性。ｂｃｌ－２反义药物与传统化疗药物协同使用有望成为解决肿瘤化疗耐药的新突破口。     

1,25二羟维生素D3治疗肿瘤研究进展

肿瘤的多药耐药是肿瘤治疗失败的主要原因之一,如何逆转肿瘤的多药耐药是目前治疗的一个重点问题。1,25二羟维生素D3对肿瘤具有预防和治疗的作用,近年的研究表明1,25二羟维生素D3联合化疗药物、放疗和内分泌治疗等方法时,可以增强这些治疗方法的效果,降低甚至逆转肿瘤细胞对化放疗的抵抗性。     

HIF-1α和VEGF在乳腺癌中作用的研究进展

缺氧诱导因子-1α（hypoxia-inducible factor-1α,HIF-1α）可诱导靶基因转录激活,在调节肿瘤血管生成、侵袭转移及耐药等方面发挥重要作用;血管内皮生长因子（vascular endothelial growth factor,VEGF）通过促进肿瘤血管和淋巴管的形成,介导肿瘤细胞的生长与存活.二者在肿瘤血管形成、侵袭转移及化疗耐药等方面有相互协调的作用,通过检测二者在肿瘤中的表达,分析二者之间的相互关系,对判断肿瘤患者的预后及指导个体化治疗有重要的临床意义.HIF-1α和VEGF在临床上均可作为乳腺癌有价值的预后指标,本文将就HIF-1α、VEGF在乳腺癌中作用的研究进展做一综述.     

Radiolabelled agents for PET imaging of tumor hypoxia

Hypoxia has been observed in a variety of human tumor types and evaluating tumor hypoxia is important because it increases resistance to radiotherapy and chemotherapy by inducing proteomic change that allow the tumor cell to survive in their hypoxic environment. One of the major proteomic changes is HIF-1 expression, and HIF-1 has become a target for anti-cancer drugs development because of its central role in hypoxia-mediated aggressiveness of tumor cells and their resistance to therapy. Since tumor hypoxia is a key mechanism that leads to resistance of treatment, a large number of challenges for hypoxia imaging including magnetic resonance, optical, and nuclear imaging have been reported. These hypoxia imaging techniques may have potential in selecting cancer patients who would benefit from treatments that overcome the presence of hypoxia. Hypoxia imaging could also be used to document whether or not and the extent to which reoxygenation of tumors occurs during cancer treatment. One of key requirements of ideal method for imaging hypoxia is that the method should be non-invasive. From an imaging perspective, PET is also one of leading tools for imaging hypoxia because of its high spatial resolution, high sensitivity, and advantages for visualizing molecular events in living human tissue. In this review, PET-based radiopharmaceuticals including (18)F-FMISO, (18)F-FETNIM, (18)F-FAZA, and radioactive Cu-ATSM were summarized from published studies about radiosyntheses, pre-clinical data, and clinical data, which are the lead contenders for human application.     

基于低氧微环境的小分子激活前药与HIF-1抑制剂研究进展

低氧是实体瘤普遍存在的特征,是肿瘤细胞增殖、转移、侵袭、产生放疗抗性的重要原因。因此,肿瘤缺氧被认为是肿瘤诊断与治疗的一个重要靶点。低氧激活前药可在缺氧微环境下通过电子还原靶向低氧区域的肿瘤细胞,产生并释放细胞毒性代谢产物,从而杀死肿瘤细胞。目前已报道的低氧激活前药主要包括硝基化合物、醌类、氮氧化物、金属配合物、偶氮化合物五大类。而低氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)也在肿瘤细胞的低氧存活与发展中扮演重要角色,抑制HIF-1可抑制其下游基因主导的肿瘤血管生成、转移、耐药等生存发展进程。当前,已有低氧激活前药与HIF-1抑制剂正处于临床试验阶段,并表现出良好的抗肿瘤活性,并有可能在未来的肿瘤诊断与治疗中发挥重要作用。     

低氧诱导因子在肿瘤干细胞介导的肿瘤发生发展中的作用

低氧及低氧诱导因子（HIFs）是肿瘤干细胞、 转移起始细胞及其分化后代在肿瘤发生发展过程中, 能够适应氧气和营养物质缺乏的主要调节因子。在白血病、 胶质母细胞瘤、 黑色素瘤、 前列腺癌、 乳腺癌、 胰腺癌等肿瘤中均发现 HIFs 的表达上调, 尤其集中表达在低氧区域。活化的 HIFs 可以诱导多种干性及多药耐药等基因的表达, 对肿瘤及干性介导的肿瘤细胞的自我更新、 能量代谢改变、 侵袭转移、 血管生成以及治疗抵抗均起着重要作用。因此, 研究 HIFs 分子在干细胞介导的不同肿瘤细胞中的靶向调节作用和代谢通路的改变, 将为肿瘤的靶向治疗提供新线索。     

Recent progress of hypoxia-modulated multifunctional nanomedicines to enhance photodynamic therapy: opportunities,challenges, and future development

Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed. Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.     

Scutellaria barbata inhibits angiogenesis through downregulation of HIF‐1 α in lung tumor

Hypoxia, a hallmark of many solid tumors, is associated with angiogenesis and tumor progression. Hypoxia‐inducible factor‐1 (HIF‐1) plays a significant role in tumor angiogenesis. In this study, the authors constructed a selective platform to screen the traditional Chinese medicine as anti‐angiogenic agent. The authors examined the molecular mechanism by which Scutellaria barbata regulates HIF‐1‐dependent expression of vascular endothelial growth factor (VEGF), which is an important angiogenic factor. Hypoxia promotes angiogenesis by increasing VEGF expression and secretion. Herein, the expression of VEGF was decreased by treatment with S. barbata in tumor cells. Meanwhile, S. barbata reduced the migration and proliferation of endothelial cells under hypoxic condition. S. barbata inhibited the expression of HIF‐1α, as well as phosphorylated their upstream signal mediators AKT. S. barbata significantly inhibited the tumor growth in vivo and immunohistochemical studies in the tumors revealed decreased intratumoral microvessel density. These results suggest that the traditional Chinese medicine therapy using S. barbata, which exerts anti‐angiogenic activities, represents a promising strategy for the treatment of tumors. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 363–370, 2014.     

Assessment of tumor tissue oxygenation: agents, methods and clinical significance

Hypoxia is a pathophysiological aspect that is characteristic for many solid tumors. It is an indicator for tumor aggressiveness and predicts poor treatment outcome. Thus, the assessment of tumor hypoxia would help clinicians to select patients for additional or more specific treatment regimens. Tumor hypoxia can be detected by invasive and noninvasive techniques. The polarographic oxygen electrode method is considered indispensable to establish the effect of antitumor therapy on hypoxia but its invasive nature prevents frequent and repeated use. Therefore, the development of noninvasive techniques is needed and has been directed towards magnetic resonance imaging (MRI) and scintigraphic imaging. Whereas MRI, though promising, is still in its infancy, scintigraphy has demonstrated its ability to depict hypoxic tumor areas. This paper reviews the state-of-the-art in this field. In addition, this paper mentions the related research and new agents to target hypoxia-related makers to interfere with tumor survival and growth.     

Hypoxia-regulated microRNAs in human cancer

Hypoxia plays an important role in the tumor microenvironment by allowing the development and maintenance of cancer cells, but the regulatory mechanisms by which tumor cells adapt to hypoxic conditions are not yet well understood. MicroRNAs are recognized as a new class of master regulators that control gene expression and are responsible for many normal and pathological cellular processes. Studies have shown that hypoxia inducible factor 1 (HIF1) regulates a panel of microRNAs, whereas some of microRNAs target HIF1. The interaction between microRNAs and HIF1 can account for many vital events relevant to tumorigenesis, such as angiogenesis, metabolism, apoptosis, cell cycle regulation, proliferation, metastasis, and resistance to anticancer therapy. This review will summarize recent findings on the roles of hypoxia and microRNAs in human cancer and illustrate the machinery by which microRNAs interact with hypoxia in tumor cells. It is expected to update our knowledge about the regulatory roles of microRNAs in regulating tumor microenvironments and thus benefit the development of new anticancer drugs.