贝伐珠单抗所致蛋白尿的研究进展

贝伐珠单抗作为血管内皮细胞生长因子(VEGF)信号通路的阻断药之一,可通过影响VEGF信号通路,抑制肿瘤新生血管的生成,从而达到抑制肿瘤生长的目的。近年来,贝伐珠单抗已被广泛应用于肿瘤的抗血管生成的治疗中,尤其是其在转移性结直肠癌、非小细胞肺癌、转移性肾细胞癌等肿瘤的治疗中疗效显著。不同于使用传统细胞毒性化疗药物产生的不良反应,使用VEGF信号通路阻断药会出现蛋白尿、高血压、出血等不良反应,而贝伐珠单抗的临床应用在很大程度上又受到蛋白尿这一不良反应的限制,不仅降低了整体的临床获益,也不利于患者的治疗及预后。使用贝伐珠单抗进行治疗是否会导致蛋白尿的发生,与患者的用药剂量、用药疗程、肿瘤类型、是否合并使用肾毒性药物、是否具有肾脏相关基础性疾病等多种因素有关。目前,对于使用贝伐珠单抗导致蛋白尿,其发生机制尚不十分明确,且无针对性的预防和治疗手段。本文就使用贝伐珠单抗而产生蛋白尿的发生原因、可能机制、影响因素和治疗方案等作一综述。     

血管紧张素转化酶抑制剂对慢性肾小球肾炎时蛋白尿的影响

早在1827年R.Bright就发现了肾脏疾病与浮肿和蛋白尿之间的关系。现已证明,肾脏疾病本身以及全身性疾病时均可出现蛋白尿。蛋白尿的程度仅提示肾功能受损的情况,而与其病因无关。 血管紧张素转化酶抑制剂(ACEI)有助于改善蛋白尿,其机制可能与改变了血压、肾小球内压以及肾小球基底膜通透性有关。 我们给慢性肾小球肾炎性高血压者ACEI,以观察其对尿中蛋白、白蛋白和IgG排清量以及肾脏血流动力学和肾素血管紧张素系统的影响。     

抗高血压治疗对有微量蛋白尿的年轻Ⅰ型糖尿病患者肾小球旁器的作用

背景和目的:观察抗高血压药对有微量蛋白尿的年轻Ⅰ型糖尿病患者肾小球旁器的作用。 材料和方法:对12名有微蛋白尿的Ⅰ型糖尿病患者随机采用血管紧张素转换酶抑制剂(组1,6人),或用β-受体抑制剂(组2,6人)进行治疗。对照组为9名有微蛋白尿的Ⅰ型糖尿病患者,未行抗高血压治疗以提供参照值(组3,9人)。在开始时和40(组1,组2)与30个月(组3)之间行肾活检。在光学显微镜下,观察塑料包埋的1μm厚连续切片,可检见肾小球旁器和     

VEGF信号通路及结直肠癌抗VEGF/VEGFR靶向治疗

化疗联合靶向药物是晚期结直肠癌的主要治疗手段。VEGF信号通路在结直肠癌发生发展中地位特殊,且针对VEGF信号通路的靶向药物临床应用广泛、疗效好。本文就VEGF信号通路及结直肠癌抗VEGF/VEGFR靶向药物作一综述。     

贝伐单抗治疗进展期非小细胞肺癌临床疗效及安全性观察

贝伐单抗是重组人源化血管内皮生长因子（vascular endothelial growth factor,VEGF）的IgG1型单克隆抗体,能与所有VEGF异构体结合,从而阻断VEGF与VEGFR结合,以抑制VEGF活性,是一种抑制血管生成的靶向治疗药物,联合化疗用于非鳞型非小细胞肺癌的一线治疗,可以延长无进展生存期及总生存期,提高有效率;2006年10月美国FDA推荐贝伐单抗联合紫杉醇/卡铂化疗方案用于非鳞型非小细胞肺癌的一线治疗。贝伐单抗治疗的安全性受到广泛关注,最常见的不良反应包括高血压、蛋白尿、血管栓塞、出血等,相关不良反应不容忽视,但高血压、蛋白尿、血管栓塞等可以通过对症处理得到控制,且与常规化疗药物不良反应不相互重叠,与化疗药物联合应用安全性较高,多数患者耐受性良好。本文就贝伐单抗治疗进展期非小细胞肺癌临床疗效及安全性进行综述。      

血管内皮生长因子和D114-Notch信号通路在肿瘤血管发生中的作用

抗肿瘤血管发生是一种全新的抗肿瘤治疗策略,目前研究最多的是寻找有效抗血管内皮生长因子（VEGF）信号通路的药物。然而VEGF抑制剂并不是对所有肿瘤有效,因此,有必要进一步探索血管发生的其他信号通路。目前,DH4-Nmch信号通路被认为是抗肿瘤血管发生的新靶点,而且VEGF和DH4-N0tch信号通路在多方面相互作用,在调控血管发生过程中发挥重要作用,对这两条通路的探索和研究,将会使治疗肿瘤的手段更为丰富。     

血管内皮生长因子和Notch信号通路与肿瘤血管生成

血管内皮生长因子(VEGF)和Notch信号通路是血管发育及肿瘤血管生成的重要机制.阻断VEGF可抑制肿瘤生长和血管生成.Notch能抑制内皮形成尖端细胞,减少血管生成.实验证明,两条通路相互作用,联合阻断VEGF和Notch信号通路可协同抑制肿瘤生长.对VEGF和Notch通路的研究,将为肿瘤临床治疗提供新的方法.     

血管内皮生长因子和Dll4-Notch信号通路在肿瘤血管发生中的作用

抗肿瘤血管发生是一种全新的抗肿瘤治疗策略,目前研究最多的是寻找有效抗血管内皮生长因子(VEGF)信号通路的药物.然而VEGF抑制剂并不是对所有肿瘤有效,因此,有必要进一步探索血管发生的其他信号通路.目前,Dll4-Notch信号通路被认为是抗肿瘤血管发生的新靶点,而且VEGF和Dll4-Notch信号通路在多方面相互作...     

肾病综合征

肾病综合征为每日蛋白尿超过3.5g/1.73m~2体表面积。肾性蛋白尿的后果不取决于基础疾病,而是常伴有水肿形成、钠潴留、高脂蛋白血症、高血栓危险性和易感染倾向。肾性蛋白尿的产生是由于肾小球滤过膜异常所致。该膜由一具有高度选择性的上有多个细孔的膜和一道电子屏障(带多价负离子的葡糖胺多糖)组成。肾小球滤过障碍病因学上在肾病综合征的一种表现形式为局灶节段性肾小球硬化,证实了一种循环的、可能由淋巴细胞产生的因     

靶向VEGF/VEGFR通路治疗胃癌的研究进展

胃癌是目前全球最常见的恶性肿瘤之一,早期诊断率低,预后差,手术及放化疗对进展期胃癌的疗效有限。自1971年Folkman首先提出实体肿瘤的发展和转移离不开新生血管后,抗血管新生方面的研究就一直是肿瘤学的热点。血管内皮生长因子（VEGF）是已知的被多种实体肿瘤分泌的、最强的血管调控生长因子和信号传递因子,VEGF高表达是胃癌的特征之一。VEGF及其受体VEGFR在胃癌的发生、发展中发挥了重要作用。因此,靶向VEGF/VEGFR信号通路的治疗有望在胃癌的综合治疗方面取得重大突破。本文就VEGF/VEGFR信号转导路径及胃癌抗血管治疗的最新研究进展作一简要综述。     

Favorable clinical course of patients experiencing bevacizumab-induced proteinuria

Nephrotic-range proteinuria, which denotes structural damage to the glomerular filtration barrier, occurs in 1-2% of bevacizumab-treated patients. The glomerular injury and subsequent proteinuria is probably due to a direct targeting of vascular endothelial growth factor (VEGF). We report a case series of six patients who developed a syndrome characterized by proteinuria and hypertension after starting therapy with bevacizumab and who experienced prolonged progression-free survival. Given that altered glomerular permeability appears to be a direct consequence of VEGF inhibition, we hypothesize that proteinuria may indeed correlate with drug efficacy. Optimizing safe and effective drug dosing is critical to achieve the best therapeutic impact due to limited treatment options for many life-threatening advanced cancers. Clinicians should be aware that the development of proteinuria might serve as a surrogate marker of bevacizumab antitumor efficacy and determine the appropriate criteria for withholding this effective anticancer therapy.     

VEGF signalling inhibition-induced proteinuria: Mechanisms,significance and management

Proteinuria is a dose-related side-effect occurring after inhibition of vascular endothelial growth factor (VEGF) signalling and may reflect severe glomerular damage. The inhibition of the VEGF signalling axis induces downexpression or suppression of nephrin, an important protein for the maintenance of the glomerular slit diaphragm, sometimes leading to nephritic syndrome and/or glomerular thrombotic microangiopathy, the main-associated kidney disease. A MEDLINE search was carried out using the following criteria: (1) all MEDLINE listings as of 01-01-2000 with abstracts; (2) English language; and (3) Humans. The following phrases were used to query the database: (proteinuria) AND (anti-VEGF OR VEGF inhibition OR bevacizumab OR sunitinib OR sorafenib OR VEGF Trap OR axitinib OR pazopanib OR AZ 2171). The references of each article identified were carefully reviewed for additional reference. The incidence of mild and asymptomatic proteinuria ranges from 21% up to 63%, but heavy proteinuria has been reported in up to 6.5% of renal cell carcinoma patients. Although discontinuation of anti-VEGF agent induced significant reduction, persistence of proteinuria is common. Although angiotensinconverting-enzyme inhibitors and/or angiotensin receptor blockers seem to be preferred, no specific recommendation for an antiproteinuric agent can be made in this context because there are no controlled studies addressing the subject. Periodic monitoring of urinary protein should be carried out in anti-VEGF-treated patients and patients showing proteinuria need special referral to nephrologists.     

Nephrotoxicity--proteinuria and hypertension--

Targeted and biological therapies have been investigated as methods of improving anticancer therapy. One approach to targeted therapy is to inhibit tumor angiogenesis, which has a critical role in the development of cancer. However, the potential for further improvement in outcomes is likely to be limited by its nephrotoxic side effects such as urinary protein and hypertension. Among the anti-angiogenesis inhibitors, the humanized monoclonal antibody, bevacizumab, directed against VEGF(vascular endothelial growth factor), is the first anti-angiogenic agent to be approved for cancer therapy, but it has a high frequency of these side effects. Hypertension could be due to a reduction of eNOS activity and rarefaction of microvessels in various tissues and organs induced by VEGF inhibition. Bevacizumab also induces proteinuria, glomerular endothelial cell detachment and suppression of nephrin, an important protein for the maintenance of the glomerular slit diaphragm, sometimes leading to nephritic syndrome and/or thrombotic microangiopathy in the glomeruli. Periodic monitoring of blood pressure and urinary protein should be necessary in patients on anti- VEGF agents. Patients showing nephrotoxicities need special referral to nephrologists and to be treated using proper anti-hypertension drugs.     

VEGF Inhibition, Hypertension, and Renal Toxicity

The use of anti-angiogenic agents as part of the therapeutic armamentarium for advanced stage solid tumors has become the standard of care in several instances, particularly for renal cell carcinoma, non-small cell lung carcinoma, colorectal carcinoma, and gastrointestinal stromal tumors. These agents primarily target vascular endothelial growth factor (VEGF) and/or its receptors, and include bevacizumab, a humanized monoclonal antibody against VEGF, as well as tyrosine kinase inhibitors that target several receptor tyrosine kinases (RTK), including VEGF receptors. These therapies, as a general class of anti-angiogenic medications, have been shown to have common adverse vascular effects attributable directly or indirectly to their anti-VEGF effects, including hypertension, renal vascular injury, often manifested by proteinuria and thrombotic microangiopathy, and congestive heart failure. Knowledge of these common side effects and their underlying mechanisms may allow for more accurate and prompt diagnoses, timely clinical interventions, and the development of rational and standard treatments. These measures may minimize patient morbidity and mortality, not only by the treatment of side effects, but also by minimizing the disruption of treatment of the underlying malignancy, as well as improving patient quality of life.     

Multitargeted receptor tyrosine kinase inhibition: an antiangiogenic strategy in non-small cell lung cancer

In the United States, the leading cause of cancer-related deaths is lung cancer, of which more than 85% of cases are categorized as non-small cell lung cancer. The process of angiogenesis, which results in the formation of vasculature, is a complex and coordinated process that is required for cancer growth and metastasis. Pathways that promote angiogenesis have been targeted as a therapeutic approach in multiple types of cancer, including non-small cell lung cancer. Of these, the vascular endothelial growth factor pathway has been the most well studied, but more recently, the platelet-derived growth factor and fibroblast growth factor pathways have been identified as regulators of angiogenesis and potential mediators of resistance to vascular endothelial growth factor inhibition. Bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor, is currently the only antiangiogenic drug approved for the treatment of non-small cell lung cancer; however, several tyrosine kinase inhibitors that target vascular endothelial growth factor receptors as well as platelet-derived growth factor receptors and/or fibroblast growth factor receptors are being developed. This article reviews the role of the fibroblast growth factor and platelet-derived growth factor pathways in angiogenesis and provides a summary of dual (e.g., sorafenib, sunitinib) and triple (e.g., BIBF 1120, pazopanib) antiangiogenic tyrosine kinase inhibitors currently in development for the treatment of non-small cell lung cancer.     

The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review

Clinical experience with vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors is rapidly increasing, and some compounds have already been approved for regular anticancer treatment.Apart from their activity, much attention has been focussed on the clinical toxicity profile of these compounds.This review describes the most frequently occurring side-effects of both antibodies and tyrosine kinase inhibitors and discusses some of the underlying mechanisms. Some practical guidelines for treatment of the side-effects are given.     

抗血管生成药物在铂耐药卵巢癌中的应用进展

化疗药物在铂耐药卵巢癌治疗中应用非常局限,近年来,多项试验表明抗血管生成药物有改善铂耐药卵巢癌患者预后的作用。本文根据作用机制的不同,把抗血管生成药物分为血管内皮生长因子抑制剂、血管内皮生长因子受体抑制剂、酪氨酸激酶抑制剂和整合素抑制剂,分别阐述其在铂耐药卵巢癌治疗中的研究进展。     

Fibrinogen E-fragment inhibits the migration and tubule formation of human dermal microvascular endothelial cells in vitro

Angiogenesis, the development of new blood vessels from an existing vascular bed, is essential for the growth and spread of malignant tumors. Several endogenous angiogenesis inhibitors have been discovered and shown to suppress endothelial cell function in vitro and tumor growth in vivo. Several of these are proteolytic fragments of larger, endogenous proteins. Here we show that a Mr 50,000 polypeptide derived from the plasmin cleavage of fibrinogen, fibrinogen E-fragment, inhibits endothelial cell migration and tubule formation induced by both proangiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in vitro.     

Inhibitory effect on expression of angiogenic factors by antiangiogenic agents in renal cell carcinoma

Since it has been widely recognised that renal cell carcinoma is refractory to standard therapies such as chemotherapy and radiotherapy, a new modality of treatment is needed. One of the potential alternative therapies for renal cell carcinoma may be inhibition of angiogenesis. In this study, we analysed the inhibitory effects of several potential agents on expression of angiogenic factors such as vascular endothelial growth factor and basic fibroblast growth factor, which are the main mediators in angiogenesis of renal cell carcinoma. We used medroxyprogesterone acetate, interferon-alpha, interferon-gamma, minocycline hydrochrolide and genistein, which are known to be antiangiogeneic. Northern blot analyses revealed that, among the five agents examined, genistein had a strong inhibitory effect on expression of vascular endothelial growth factor mRNA and basic fibroblast growth factor mRNA. Medroxyprogesterone acetate and interferon-alpha did not significantly decrease the level of either vascular endothelial growth factor mRNA or basic fibroblast growth factor mRNA. Interferon-gamma and minocycline had mild inhibitory effects on vascular endothelial growth factor mRNA and basic fibroblast growth factor mRNA expression. Genistein also inhibited both vascular endothelial growth factor mRNA and basic fibroblast growth factor mRNA expression after treatment with epidermal growth factor and hypoxia. These findings suggest that one of the mechanisms of the inhibition of angiogenesis by genistein is suppression of the expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor in renal cell carcinoma.     

Antiangiogenic drugs in non-small cell lung cancer treatment

PURPOSE OF REVIEW: A promising therapeutic target is the vascular endothelial growth factor pathway - a key mediator of tumor angiogenesis - which is important in tumor growth, invasion, and metastasis. This review focuses on the available clinical data on drugs targeting the vascular endothelial growth factor - vascular endothelial growth factor receptor pathway in the treatment of non-small cell lung cancer. RECENT FINDINGS: The therapeutic value of inhibiting the vascular endothelial growth factor pathway has been demonstrated by using drugs that prevent vascular endothelial growth factor receptor binding and by using drugs that inhibit receptor activation. Two antiangiogenic drugs exemplify these mechanisms: bevacizumab (Avastin; Genentech, South San Francisco, California, USA), a humanized monoclonal antibody that acts by binding and neutralizing vascular endothelial growth factor; and ZD6474 (Zactima; AstraZeneca, Macclesfield, UK), a small-molecule inhibitor of vascular growth factor receptor and epidermal growth factor receptor tyrosine kinase activity. Recently, the first results of a large, phase III randomized clinical trial of bevacizumab in combination with platinum-based doublet chemotherapy have been reported in patients with nonsquamous non-small cell lung cancer. SUMMARY: The inhibition of tumor angiogenesis is a key therapeutic strategy that holds great promise for the advancement of metastatic lung cancer therapy. The combination of bevacizumab and conventional chemotherapy could offer a new therapeutic option in selected non-small cell lung cancer histotypes.