抗肿瘤血管生成类药物致蛋白尿的机制及临床诊治

血管内皮生长因子(vascular endothelial growth factor,VEGF)及其受体(vascular endothelial growth factor receptor,VEGFR)在生理和病理性血管生成中发挥关键作用。由于恶性肿瘤生长离不开新生血管支持,因此抑制VEGF/VEGFR系统的抗肿瘤血管生成药物已成为肿瘤药物治疗重要手段之一。随着药物在临床上被广泛应用,部分患者在用药过程中发生以蛋白尿为表现的肾毒性,其发病机制尚不明确。现就抗肿瘤血管生成药物临床使用致蛋白尿的发生率、机制及临床诊治作一综述,旨在为临床用药提供参考。     

以VEGF／VEGFR为靶点的肝癌药物研究进展

肝癌细胞的生长、转移依赖新生血管的形成。血管内皮生长因子（vEGF）是最有效的促血管生长因子。以VEGF及其受体VEGFR为靶点治疗肝癌是肝癌药物研究的热点。当前肝癌治疗药物疗效差、易产生耐药性、副作用大,而不同药物之间的综合治疗能提高肝癌治疗效果。本文对以VEGF／VEGFR为靶点的肝癌药物研究进行综述。     

血管内皮生长因子及受体在肿瘤发病机制中的研究进展

血管内皮生长因子（vascular endothelial growth factor,VEGF）是最有效的血管生长调节因子,在血管和淋巴管内皮细胞的生长和分化中起重要作用.由于VEGF在肿瘤基质细胞中的高表达及血管生成中的重要作用,成为抗肿瘤血管生成的主要作用靶点.现将VEGF及受体在血管、淋巴管生成,肿瘤生长、转移中的作用机制及其表达调控的研究进展综述如下.     

靶向血管内皮生长因子/血管内皮生长因子受体-2的血管生成抑制剂

血管内皮生长因子(VEGF)及血管内皮生长因子受体-2(VEGFR-2)是调节血管生成、内皮细胞增殖和迁移等的关键调控因子。通过阻断VEGF与VEGFR-2的结合可抑制新生血管形成,而新生血管的形成是肿瘤生长和转移的基础。介绍VEGF/VEGFR-2在血管形成中的作用,以及具有抗肿瘤作用的靶向VEGF/VEGFR-2的血管生成抑制剂的研究近况。     

贝伐单抗临床研究进展

血管内皮生长因子(VEGF)对肿瘤生长、转移十分重要。抗VEGF受体的人源单克隆抗体贝伐单抗,可抑制肿瘤血管生成,因而起到抑制肿瘤生长的作用。以血管内皮生长因子作为治疗靶点,提供了恶性肿瘤治疗的又一新的策略。     

靶向血管内皮生长因子及其受体的抗肿瘤药物研究进展

血管生成对肿瘤的生长和转移起着关键作用,血管内皮生长因子（VEGF）及其受体信号通路是调节肿瘤新生血管生成的重要途径,因此,近年来以VEGF及其受体为作用靶标的抗肿瘤血管生成治疗已经成为研究热点,目前已有多种药物上市或处于临床试验阶段。本文主要综述了VEGF及其受体在肿瘤血管生成调节机制中的作用,同时着重介绍靶向VEGF及其受体的抗肿瘤药物的新近研究进展、临床应用及存在的问题。     

血管内皮生长因子受体抑制剂——Axitinib

近年来,在抗肿瘤药的研制中,靶向血管生成和血管内皮生长因子(VEGF)的药物已成为热点.一些抗VEGF的单克隆抗体,如治疗转移性结肠直肠癌的贝伐单抗(bevacizumb)和小分子、多靶向[包括靶向于VEGF受体(VEGFR)]的激酶抑制剂,如舒尼替尼(sunitinib) 、索拉非尼(sorafenib)等陆续被批准上市.     

VEGF165_b的抗血管生成作用在肾癌发生、发展中的研究进展

肾癌是一种高度血管化的恶性实性肿瘤,其生长和转移依赖于新生血管的形成,而血管形成主要是由促血管生成因子和抑制因子调控失衡、促血管生成因子增多所致。血管内皮生长因子(VEGF)亚型VEGF165是机体内含量最多,生物活性最强的促血管生成因子,且在肾癌组织中高表达,与肿瘤的生长、转移密切相关。最新研究发现一种新的VEGF异构体VEGF165b具有抑制VEGF165介导的血管生成作用,有可能成为肾癌治疗过程中新的作用靶点,具有重要的临床应用价值。本文对VEGF165b的结构、作用机制进行综述。     

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。     

血管内皮生长因子及其受体在抗肿瘤治疗应用的研究进展

肿瘤的生长依赖肿瘤新生血管的形成。血管内皮生长因子（VEGF）是一类能促进血管生成的细胞因子，能诱导细胞的有丝分裂和调节内皮细胞的通透性。VEGF及其受体介导的肿瘤血管新生在肿瘤的生长和转移中具有重要的作用。本文综述了VEGF及其受体的分类、作用机制及在抗肿瘤治疗中的应用。     

The clinical application of fruquintinib on colorectal cancer

ABSTRACT

Introduction: Anti-angiogenetic agents are currently the most commonly used drugs for the treatment of colorectal cancer (CRC) patients, including various inhibitors targeting the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and VEGF receptors (VEGFRs). Fruquintinib (HMPL-013), a highly selective and long-term small-molecule inhibitor of VEGFR (VEGFR1, 2, and 3) was recently approved in China for CRC treatment. Clinical studies have shown it has many advantages, such as low off-target toxicity, good drug tolerance, and strong effect.

Areas covered: In the review, the molecular structure, mechanism of action, pharmacokinetics, clinical efficacy, and safety of fruquintinib are introduced in detail. The potential clinic application on non-small cell lung cancer (NSCLC) and gastric cancer is also discussed.

Expert commentary: Fruquintinib was approved for patients with metastatic colorectal cancer (RAS wild type) who have previously received fluorouracil, oxaliplatin, and irinotecan-based chemotherapy and who have received or are not suitable for anti- VEGF therapy and anti- EGFR therapy. As a novel, therapeutic approach to CRC, Fruquintinib could be used as a third-line drug for the treatment of CRC patients. Due to drug resistance during the long-term therapy, the combination of fruquintinib with other targeted therapy drugs may be an effective option for CRC treatment.     

真菌单模块非核糖体肽合成酶的基因组挖掘与天然产物研究

真菌非核糖体肽(nonribosomal peptides, NRPs)是一类重要的次级代谢产物,其中不乏结构和功能特殊、可作药用的化合物。本文介绍了组成非核糖体合成酶(nonribosomal peptide synthases, NRPSs)各结构域的功能,综述了已有报道的两种单模块非核糖体合成酶,即仅含有腺苷化结构域(adenylation domain, A结构域)、巯基化结构域(thiolation domain, T结构域)、硫酯酶结构域(thioesterase domain, TE结构域)的NRPSs：A-T-TE和仅含有腺苷化结构域、巯基化结构域、一个还原酶结构域(reductase domain, R结构域)的NRPSs：A-T-R的生物合成产物,并结合生物信息学分析推测了第3种含有腺苷化结构域、巯基化结构域、两个还原酶结构域的单模块NRPSs：A-T-R-R可能合成的产物结构。     

VEGF-VEGFR Signals in Health and Disease

Vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) system has been shown to play central roles not only in physiological angiogenesis, but also in pathological angiogenesis in diseases such as cancer. Based on these findings, a variety of anti-angiogenic drugs, including anti-VEGF antibodies and VEGFR/multi-receptor kinase inhibitors have been developed and approved for the clinical use. While the clinical efficacy of these drugs has been clearly demonstrated in cancer patients, they have not been shown to be effective in curing cancer, suggesting that further improvement in their design is necessary. Abnormal expression of an endogenous VEGF-inhibitor sFlt-1 has been shown to be involved in a variety of diseases, such as preeclampsia and aged macular degeneration. In addition, various factors modulating angiogenic processes have been recently isolated. Given this complexity then, extensive studies on the interrelationship between VEGF signals and other angiogenesis-regulatory systems will be important for developing future strategies to suppress diseases with an angiogenic component.     

Building on a foundation of VEGF and mTOR targeted agents in renal cell carcinoma

Since late 2005 six new drugs have been approved by the Food and Drug Administration (FDA) for the treatment of metastatic renal cell carcinoma (RCC). However, the similarity of these agents with regard to mechanism of action makes it unclear if each agent has unique clinical utility. This flurry of drug development activity stems from the understanding of the central role that loss of von Hippel Lindau (VHL) gene function plays in the pathophysiology of clear cell RCC. The first agent to establish the therapeutic value of targeting the downstream consequences of VHL loss of function was a vascular endothelial growth factor (VEGF) directed monoclonal antibody, bevacizumab. Following the initial observations with bevacizumab, three VEGF receptor (VEGFR) tyrosine kinase inhibitors, with varied spectra beyond VEGFR, have been successfully developed clinically. Unanticipated clinical activity was observed with inhibitors of mTOR, a central component of the nutrient-sensing PI3 kinase pathway, in RCC. Subsequent work identified that mTOR also regulates the expression of hypoxia inducible factor (HIF), which is regulated by VHL outside of the setting of inactivating mutations or deletions. This appears to tie all of the six approved therapies to the direct consequences of loss of VHL function in clear cell RCC. It remains poorly understood to what extent these therapies differ from one another. Although the outcome of patients with metastatic RCC has been substantially altered with administration of the currently available therapies, the proper selection of currently available therapy, rational development of agents with novel mechanism of action and development of predictive biomarkers of response remains a challenge.     

缺氧诱导因子-1α及其抑制剂的研究进展

缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)在缺氧肿瘤细胞尤其是实体瘤中都存在着过度表达,它能够控制下游100多种基因的表达,包括血管内皮生长因子(VEGF)、葡萄糖转移酶-1(GLUT-1)、酪氨酸激酶(c-Met)等,对肿瘤细胞的增殖、转移、侵入、凋亡以及糖代谢都有至关重要的作用。已经证明许多已经上市的和进入临床研究的药物都具有HIF-1α抑制活性。近几年,设计合成的多种类型的新型小分子HIF-1抑制剂,有望成为新一类抗肿瘤药物。本文主要对近年来设计合成的新型HIF-1α抑制剂进行综述。     

多靶点酪氨酸激酶抑制剂舒尼替尼的研究进展

近年来各种酪氨酸激酶抑制剂不断涌现,以酪氨酸激酶抑制剂为代表的分子靶向治疗已成为抗肿瘤研究的热点.舒尼替尼(sunitinib,商品名Sutent)是一种小分子多靶点酪氨酸激酶抑制剂,对血小板衍生生长因子受体(PDGFR)、血管内皮生长因子受体(VEGFR)、干细胞因子受体(C-Kit)等多种受体酪氨酸激酶具有抑制作用,已于2006年1月被美国FDA批准用于临床上晚期肾细胞癌(RCC)和对伊马替尼(ima-tinib)耐药和(或)治疗失败的胃肠道间质瘤(GIST)的治疗,并在其他多种肿瘤的临床试验中也显示显著抗肿瘤活性,文中综述了该药的临床前研究及临床研究进展.     

Vascular endothelial growth factor tyrosine kinase inhibitors

Tyrosine kinase inhibitors of the vascular endothelial growth factor (VEGF) receptor remain an attractive area of research in cancer. Merck has had an ongoing programme related to small-molecule inhibitors of the VEGF receptor kinase and has filed numerous applications in this area. The present application relates to a salt of a compound claimed explicitly in a previous application from Merck. The present application is focused on hydrochloride salts of this compound and claims several polymorphs of this salt. Such applications directed to specific polymorphs usually indicate a compound that may be of significant interest to the Merck VEGF programme.