抗血管生成因子Angiostatin与Endostatin作用下肿瘤血管生成的二维数值模拟

目的数值模拟抗血管生成因子Angiostatin和Endostatin对肿瘤血管生成的影响。方法建立肿瘤内外血管生成的二维离散数学模型。模型耦合两种抗血管生成因子Angiostatin和Endostatin的抑制效应,数值模拟在促血管生成因子诱导下肿瘤微血管网生成,讨论血管生成抑制因子的影响。结果抗血管生成因子Angiostatin对肿瘤内外血管网络生成的速度和成熟度有抑制作用。抗血管生成因子Angiostatin和Endostatin耦合作用时,在肿瘤血管生成的早期有明显的抑制效应;在肿瘤血管生成的中后期,它们可以降低肿瘤血管化程度。结论本文模型能够较好的模拟抗血管生成因子Angiostatin和Endostatin对内皮细胞迁移和增殖的抑制作用。     

AAV-mediated persistent bevacizumab therapy suppresses tumor growth of ovarian cancer

Rationale

Anti-angiogenesis therapies such as bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), have been used against ovarian cancer, but transient and low peritoneal drug levels are likely a factor in treatment failure. We hypothesized that a single administration of adeno-associated virus (AAV)-mediated intraperitoneal expression of bevacizumab would direct persistent expression and suppress growth and metastasis of ovarian cancer.

Methods

AAVrh.10BevMab, a rhesus serotype 10 adeno-associated viral vector coding for bevacizumab, was evaluated for the capacity of a single intraperitoneal administration to persistently suppress peritoneal tumor growth in an intraperitoneal model of ovarian carcinomatosis with human ovarian cancer cells in nude immunodeficient mice.

Results

The data demonstrates that AAVrh10.BevMab mediates persistent and high levels of bevacizumab in the peritoneal cavity following a single intraperitoneal administration in mice. In AAVrh10.BevMab treated A2780 human ovarian cancer-bearing mice, tumor growth was significantly suppressed (p < 0.05) and the area of blood vessels in the tumor was decreased (p < 0.04). Survival of mice with A2780 xenografts or SK-OV3 xenografts was greatly prolonged in the presence of AAVrh10.BevMab (p < 0.001). Administration of AAVrh10.BevMab 4 days after A2780-luciferase cell implantation reduced tumor growth (p < 0.01) and increased mouse survival (p < 0.0001). Combination of AAVrh10.BevMab with cytotoxic reagents paclitaxel or topotecan proved to be more effective in increasing survival than treatment with cytotoxic reagent alone.

Conclusion

A single administration of AAVrh10.BevMab provides sustained and high local expression of bevacizumab in the peritoneal cavity, and significantly suppresses peritoneal carcinomatosis and increases survival in an ovarian cancer murine model.     

Novel approaches in the therapy of metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.     

Renal Effects of Anti-angiogenesis Therapy: Update for the Internist

Angiogenesis has become an innovative target in cancer therapy. Agents that inhibit vascular endothelial growth factor (VEGF), one of the most potent promoters of angiogenesis, and its receptor have significant implications for clinical practice. Bevacizumab, sorafenib, sunitinib and other anti-VEGF drugs are frequently complicated by mild proteinuria and hypertension. Other unique renal effects, such as high-grade proteinuria and acute kidney injury, have been described. The most common histopathologic kidney lesion is thrombotic microangiopathy, with other glomerular lesions and interstitial nephritis occurring less frequently. The mechanism for anti-VEGF therapy-induced hypertension is not well understood; however, nitric oxide pathway inhibition, rarefaction, and oxidative stress may be important in its pathogenesis. Glomerular injury may develop from loss of VEGF effect on maintaining the filtration barrier. Adverse effects of anti-VEGF class of drugs are manageable but require close attention and follow-up. Understanding the fundamentals of anti-VEGF drugs' mechanism of action and their clinical implications is crucial when caring for patients receiving anti-VEGF therapy.     

Indenoisoquinoline derivatives as topoisomerase I inhibitors that suppress angiogenesis by affecting the HIF signaling pathway

Both Topoisomerase I and angiogenesis factors have caught pharmaceutical chemists’ attention in antitumor chemotherapy field. A series of indenoisoquinoline derivatives with high Top I inhibitory from our previous work were evaluated for their anti-angiogenesis property using classic in vitro and vivo models. The results demonstrated that all the compounds could significantly decrease the proliferation of endothelial cells in a concentration-dependent manner. Besides, compound 1 exerted marked inhibition of angiogenesis in vivo and in vitro models. The HIF signaling pathway in HUVECs was affected by compound 1 in a time-dependent manner. These data suggest that the tested compound 1 could serve as promising lead compound for further development and optimization.     

Vascular dynamics in relation to immunolocalisation of VEGF-A, VEGFR-2 and Ang-2 in the bovine corpus luteum

Vascular dynamics during development and regression of the bovine corpus luteum were investigated morphometrically in relation to immunolocalisation of vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor 2 (VEGFR-2) and angiopoietin 2 (Ang-2) in the different cell types. Angiogenesis and remodelling of the capillary network between day 8 and 17 of the oestrous cycle was driven by luteal cells, which were highly immunopositive for VEGF-A. Thereafter, immunoreactivity for VEGF-A and VEGFR-2 was mainly found in vascular smooth muscle cells, the predominant cell type in late luteolysis. During early regression, apoptosis of luteal and endothelial cells was closely correlated, resulting in a significant decrease of capillarity. In late regression, an increase in capillary density was found, suggesting that regression and transformation into the corpus albicans requires adequate perfusion. In the phases of vascular remodelling, i.e. mature and late regressing corpus luteum, high scores of Ang-2-immunopositive endothelial and smooth muscle cells were found. Therefore, it may be hypothesised that Ang-2 supports the angiogenic effects of VEGF-A in these luteal stages. Results emphasise that precise staging and a differentiated view on the cellular populations is important in evaluating the controlled regression and transformation of the corpus luteum.     

靶向PKM2干扰质粒联合重组人血管内皮抑素治疗肺癌的实验研究

目的 研究丙酮酸激酶同工酶M2(PKM2)干扰质粒联合重组人血管内皮抑素是否能增强单药的抗癌作用.方法 免疫荧光检测A549细胞内PKM2蛋白表达,蛋白印迹检测PKM2质粒干扰效果.建立裸鼠皮下A549肺癌模型,将25只荷瘤小鼠随机平均分为5组:生理盐水组(NS组)、无关序列干扰质粒组(psh-Control组)、PK...     

Design,synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.     

人内皮抑素基因导入对裸鼠舌鳞癌移植瘤的抑制影响

目的:探讨经体内注入人内皮抑素(humanendostatin,hES)基因治疗口腔鳞癌的可行性。方法:荷瘤人舌鳞癌Tca8113细胞裸鼠瘤体内和肌内分别注射含hES的基因质粒,观察转入hES基因对舌鳞癌移植瘤生长的影响,免疫组织化学检测肿瘤组织中hES及血管内皮细胞生长因子(vascularvesselendotheliacellgrowthfactor,VEGF)的表达,Weidern法行肿瘤微血管密度(microvesseldensity,MVD)计数,流式细胞仪检测肿瘤细胞凋亡率,采用精确概率法和单因素方差分析进行统计学处理。结果:荷瘤注射hES后第16天,瘤体注射组抑瘤率为75.0%,肌内注射组抑瘤率为66.1%(P<0.01)。免疫组织化学检测结果显示,hES在瘤体注射组和肌内注射组肿瘤中的表达率分别为90.0%和85.0%,均高于对照组的20.0%(P<0.01)。2实验组肿瘤MVD值分别为18.60±3.44和16.70±2.63,均低于对照组的22.40±3.41(P<0.01)。流式细胞仪检测发现,瘤体注射和肌内注射hES基因质粒后,肿瘤细胞凋亡率分别为11.36%±3.20%和8.08%±2.00%,均高于对照组的1.80%±0.50%(P<0.01)。结论:注射hES基因具有抑制舌鳞癌Tca8113细胞移植瘤生长的效应。     

Microarray-based Analysis of Anti-angiogenic Activity of Demethoxycurcumin on Human Umbilical Vein Endothelial Cells: Crucial Involvement of the Down-regulation of Matrix Metalloproteinase

cDNA microarray-based gene expression analysis has been successfully employed to explore the action mechanism and to validate the targets of several drugs. In the present study, we evaluated anti-angiogenic activity of demethoxycurcumin (DC), a structural analog of curcumin, isolated from Curcuma aromatica , and investigated the effect of DC on genetic reprogramming in cultured human umbilical vein endothelial cells (HUVECs) using cDNA microarray analysis. Of 1024 human cancer-focused genes arrayed, 187 genes were up-regulated and 72 genes were down-regulated at least 2-fold by DC. Interestingly, 9 angiogenesis-related genes were down-regulated over 5-fold in response to DC, suggesting that the genetic reprogramming was crucially involved in anti-angiogenesis by the compound. To verify the results obtained from cDNA microarray analysis, matrix metalloproteinase-9 (MMP-9), the product of one of the angiogenesis-related genes down-regulated over 5-fold by DC, was investigated using gelatin zymography. DC potently inhibited the expression of MMP-9, yet showed no direct effect on its activity. These data show that gene expressional change of MMP-9 is a major mediator for angiogenesis inhibition by DC. All genes identified and microarray data are available on the web at http://dasan.sejong.ac.kr/bioprobe/ .