Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

Immunotherapy combined with anti-angiogenic drugs and chemotherapy in negative driver gene and advanced non-small cell lung cancer / 中国临床药理学与治疗学

AIM: To investigate the application value of immunotherapy combined with anti-angiogenic drugs and chemotherapy in negative driver gene and advanced non-small cell lung cancer (NSCLC). METHODS: A total of 48 patients with advanced NSCLC and negative driver genes were included and randomly divided into two groups according to 1:1. The observation group received immunotherapy combined with anti-angiogenic drugs and chemotherapy. The control group received conventional standard chemotherapy. The differences between the two groups were analyzed in drug toxicity, side effects and survival status. RESULTS: Objective response rate (ORR) and disease control rate (DCR) were compared to evaluate the short-term efficacy. There was no statistical difference in ORR between the two groups. DCR in the observation group was higher than that in the control group, the difference was significant (P<0.05). The probability of hypertensive proteinuria and hand-foot syndrome in the observation group was significantly higher than that in the control group (P< 0.05). Compared with the control group, the observation group could prolong the mPFS mOS of the patients (P<0.05). CONCLUSION: Immunotherapy combined with anti-angiogenic drugs and chemotherapy can improve the efficacy of negative driver gene and advanced NSCLC, which is tolerated by patients and worthy of clinical application.

Expert consensus on off-label use of small molecule anti-angiogenic drugs in the treatment of metastatic breast cancer / 中华肿瘤杂志

Breast cancer is the most common cancer in the world, and 5-year survival rate of metastatic breast cancer is about 20%. The treatment of metastatic breast cancer is mainly chemotherapy, endocrine therapy and targeted therapy. However, after multiline treatment, patients with MBC especially the triple negative breast cancer face the problem of drug resistance. Tumor angiogenesis theory suggests that blocking angiogenesis can inhibit tumor growth and migration. Based on this, angiogenesis treatment strategy is proposed. Antiangiogenic drugs mainly include biological macromolecular drugs targeting vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) and small molecule VEGFR inhibitors. Angiogenesis is known to play a key role in the growth and metastasis of breast cancer. Therefore, anti-angiogenetic therapy has potential in metastatic breast cancer patients. Since the approval of tumor drug indications by NPMA in China is often later than the release of the latest research data, the National Health Commission issued "the guiding principles for the clinical application of new antitumor drugs" in 2020. The principle pointed out that under special circumstances such as the absence of better treatment, medical institutions should manage the usage of drugs that are not clearly defined in the instructions but have evidence-based data. Based on the latest research progress in breast cancer, the consensus writing expert group collated published reports, international academic conferences, conducted analysis, discussion and summary, collected data on the use of small molecule anti-vascular targeting drugs for advanced breast cancer, and formulated "expert consensus on the application of small molecule anti-angiogenic drugs in the treatment of advanced breast cancer" . For clinicians' reference only.

The Advance in Research into Immunotherapy for Neuroendocrine Carcinoma of Digestive System / 罕见病研究

Gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is a rare heterogeneous tumor. The heterogeneity in pathology, differentiation, grade and clinical stages results in different prognosis and treatment strategy. Patients with recurrent or metastatic NEN have limited treatment options and poor prognosis.Programmed cell death 1(PD-1) blockade has played indispensable roles in management of cancers recently.Immunotherapy is being explored in NENs in the world with emerging clinical trials. The results of the trials provide evidence and guidance in the application of NEC.The article analizes and summarizes of the findings of major investigations in this field.

Advances in immunotherapy for neuroendocrine neoplasms / 中华胃肠外科杂志

Neuroendocrine neoplasms (NEN) is a rare and heterogeneous tumor. Different pathologic morphology, differentiation, grade and clinical stages of the tumors had various treatment and prognosis. Patients with recurrent or metastatic NEN have limited treatment options and poor prognosis. In recent years, PD-1 pathway blockade has become integral components of disease management for many cancers. Immunotherapy is being explored in NEN. Studies have shown that the efficacy of immune monotherapy in NEN is limited, and it can be considered for selected patients. Biomarkers for predicting efficacy of immunotherapy include PD-L1 expression, TMB-H, MSI-H/dMMR, etc. Combined regimens of anti-CTLA-4 and anti-PD-1/PD-L1 inhibitors, and immune checkpoint inhibitor combined with anti-angiogenic drugs or chemotherapy are promising in patients with NEN, and it is worthwhile to further explore of the responding populations.

P-I metalloproteinases and L-amino acid oxidases from Bothrops species inhibit angiogenesis

Snake venoms are composed of pharmacologically active proteins that are evolutionarily diverse, stable and specific to targets. Hence, venoms have been explored as a source of bioactive molecules in treating numerous diseases. Recent evidences suggest that snake venom proteins may affect the formation of new blood vessels. Excessive angiogenesis has been implicated in several pathologies including tumours, diabetic retinopathy, arthritis, inter alia. In the present study, we have examined the effects of P-I metalloproteinases isolated from Bothrops moojeni (BmMP-1) and Bothrops atrox (BaMP-1) and L-amino acid oxidases (LAAO) isolated from B. moojeni (BmLAAO) and B. atrox (BaLAAO) on biochemical and functional aspects of angiogenesis. Methods: P-I metalloproteinases and LAAO were purified from venom by molecular size exclusion and ion-exchange chromatography and subsequently confirmed using mass spectrometry. The P-I metalloproteinases were characterized by azocaseinolytic, fibrinogenolytic and gelatinase activity and LAAO activity was assessed by enzyme activity on L-amino acids. Influence of these proteins on apoptosis and cell cycle in endothelial cells was analysed by flow cytometry. The angiogenic activity was determined by in vitro 3D spheroid assay, Matrigel tube forming assay, and in vivo agarose plug transformation in mice. Results: P-I metalloproteinases exhibited azocaseinolytic activity, cleaved α and partially β chain of fibrinogen, and displayed catalytic activity on gelatin. LAAO showed differential activity on L-amino acids. Flow cytometry analysis indicated that both P-I metalloproteinases and LAAO arrested the cells in G0/G1 phase and further induced both necrosis and apoptosis in endothelial cells. In vitro, P-I metalloproteinases and LAAO exhibited significant anti-angiogenic properties in 3D spheroid and Matrigel models by reducing sprout outgrowth and tube formation. Using agarose plug transplants in mice harbouring P-I metalloproteinases and LAAO we demonstrated a marked disruption of vasculature at the periphery. Conclusion: Our research suggests that P-I metalloproteinases and LAAO exhibit anti-angiogenic properties in vitro and in vivo.(AU)

Review on the Combination Strategy of Anti-angiogenic Agents and Other Anti-tumor Agents in Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

Treatments for advanced non-small cell lung cancer (NSCLC) include chemotherapy, targeted therapy, and immunotherapy represented by immune checkpoint inhibitors. However, the efficacy of monotherapy is still limited. Nowdays, combination strategy has drawn great attention. Anti-angiogenic agents are widely used in treating advanced NSCLC, which can not only suppress the growth and metastasis of tumor by suppressing tumor vessels, and also have synergic effect with other anti-tumor agents because they can normalize vessels and regulate immune micro-environment. This article summarizes the underlying mechanism of combining anti-angiogenic agents and other anti-tumor agents, reviews the clinical trials on the combination strategy including monoclonal antibodies and tyrosine kinase inhibitor, so as to provide a potential strategy for treating advanced NSCLC.
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Research Progress of Anti-angiogenic Agents Combined with Immunotherapy in Patients with Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

Lung cancer has the highest incidence rate and mortality in China, even in the world, and non-small cell lung cancer (NSCLC) accounts for about 85%. The growth and metastasis of tumor depend on the generation of blood vessels, and anti-angiogenic therapy is playing an increasingly important role, however, no significant improvement was observed in the underwent anti-angiogenic agents used for patients alone. In recent years, the application of immune checkpoint inhibitor (ICI) has significantly improved the prognosis of some lung cancer patients, however, the objective response rate of patients receiving ICI alone is low. While anti-angiogenic agents and ICI both regulate the tumor immune microenvironment and have a potential synergistic mechanism, showing a bright prospect in the combined application of anti-tumor therapy. In this review, we focused on the research and application of anti-angiogenic agents in combination with ICI in advanced non-small cell lung cancer.

A case of von Hippel-Lindau disease with multi-organ involvement: a rare case report

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome manifested by a spectrum of tumours in the central nervous system (CNS) and other visceral organs. We herein report a case of 35 years aged newly diagnosed diabetic female patient presented with headache, gait instability, loss of vision in both eyes, left sided hearing impairment and subsequently diagnosed to have VHL disease. The pathophysiology involves the inactivation of the VHL tumour suppressor gene. Early recognition and treatment remains the mainstay of management. Even many years after the complete tumour excision, newer neoplasms may develop. Increasing knowledge about the molecular enabled us to investigate the role of anti-angiogenic drugs. Continuous surveillance at regular interval must be conducted in patients with VHL disease.

Multi-disciplinary management for metastatic renal cell carcinoma in the ear of targeted therapy: a single center experience / 中华泌尿外科杂志

Objective To report the experience on the multi-disciplinary management of metastatic renal cell (mRCC) patients in a single center.Methods Data of 168 mRCC patients treated by multidisciplinary team (MDT) at Sun Yat-sen University Cancer Center from December 2007 to February 2019 was retrospectively analyzed.Three treatment groups were identified,including 76 patients with 55 males and 21 females,received anti-angiogenic agents alone (Group A),66 patients with 55 males and 11 males,received anti-angiogenic agents plus local therapy (Group B)and 26 patients,with 19 males and 7 females,received anti-angiogenic agents plus immunotherapy and local therapy (Group C).The Sunitinib,Sorafenib,Axitinib were chosen for the TKI.The Pembrolizumab was used for immunotherapy.The stereotactic body radiation therapy and surgical excision were considered as the local therapy.The study aims to compare the age,gender,IMDC score,pathology,nbephrectomy,adverse events,progression-free survival and overall survival (OS).Results Of all patients,the median follow-up duration was 23 months (ranging 6-117 cmonths).The PFS was 18.3 months and median OS was 33.5 months.The 2 years and 5 years survival rate was 66％ and 35％,respectively.The median OS of Group A,B and C were 29.8 months,44.6 months and not reached.2y-OS was 58％,67％ and 89％,while 5y-OS 12％,46％ and 57％.There was no difference in age,gender,IMDC score,pathology,synchronous metastases or nephterectomy between the three groups.The prognostic result in TKI based combination therapy was superior to TKI therapy alone,which the 5y-OS was 51％ and 11％,respectively.The prognostic result in group C's moderate-high risk mRCC patients was superior to group A and B.The median OS in TKI + DC and CIK + Pembrolizumab was 49.1 months and 53.1 months.On univariate analyses,IMDC score,nephrectomy and treatment group was associated with OS (P ＜ O.05).On multivariate analyses,treatment group,nephrectomy was associated with OS (P ＜ O.05).The risk of death of Group C decreased about 60％ [HR O.39 (0.17,0.89),P =O.026].78 (46.4％)patients on TKI alone and 16 (61.5％) patients treated with TKI plus immunotherapy had Grade 3 or 4 adverse events.16 (20.3％) patients had Clavien IⅢ-V toxicity after surgical procedures.6 (5.7％) patients had Grade 3 toxiciy after SBRT.Conclusions Patients treated with combined therapy had better survival than those treated with anti-angiogenic agents alone.MDT approach could bring survival benefit to mRCC patients.

Multi-disciplinary management for metastatic renal cell carcinoma in the ear of targeted therapy: a single center experience / 中华泌尿外科杂志

Objective@#To report the experience on the multi-disciplinary management of metastatic renal cell (mRCC) patients in a single center.@*Methods@#Data of 168 mRCC patients treated by multi-disciplinary team (MDT) at Sun Yat-sen University Cancer Center from December 2007 to February 2019 was retrospectively analyzed.Three treatment groups were identified, including 76 patients with 55 males and 21 females, received anti-angiogenic agents alone (Group A), 66 patients with 55 males and 11 males, received anti-angiogenic agents plus local therapy (Group B)and 26 patients, with 19 males and 7 females, received anti-angiogenic agents plus immunotherapy and local therapy (Group C). The Sunitinib, Sorafenib, Axitinib were chosen for the TKI. The Pembrolizumab was used for immunotherapy. The stereotactic body radiation therapy and surgical excision were considered as the local therapy. The study aims to compare the age, gender, IMDC score, pathology, nbephrectomy, adverse events, progression-free survival and overall survival (OS).@*Results@#Of all patients, the median follow-up duration was 23 months (ranging 6-117 cmonths). The PFS was 18.3 months and median OS was 33.5 months. The 2 years and 5 years survival rate was 66% and 35%, respectively. The median OS of Group A, B and C were 29.8 months, 44.6 months and not reached. 2y-OS was 58%, 67% and 89%, while 5y-OS 12%, 46% and 57%.There was no difference in age, gender, IMDC score, pathology, synchronous metastases or nephterectomy between the three groups. The prognostic result in TKI based combination therapy was superior to TKI therapy alone, which the 5y-OS was 51% and 11%, respectively. The prognostic result in group C's moderate-high risk mRCC patients was superior to group A and B. The median OS in TKI+ DC and CIK+ Pembrolizumab was 49.1 months and 53.1 months. On univariate analyses, IMDC score, nephrectomy and treatment group was associated with OS (P<0.05). On multivariate analyses, treatment group, nephrectomy was associated with OS (P<0.05). The risk of death of Group C decreased about 60% [HR 0.39 (0.17, 0.89), P=0.026]. 78 (46.4%) patients on TKI alone and 16 (61.5%) patients treated with TKI plus immunotherapy had Grade 3 or 4 adverse events. 16 (20.3%) patients had Clavien Ⅲ-Ⅳ toxicity after surgical procedures. 6 (5.7%) patients had Grade 3 toxiciy after SBRT.@*Conclusions@#Patients treated with combined therapy had better survival than those treated with anti-angiogenic agents alone. MDT approach could bring survival benefit to mRCC patients.

Advances in targeted therapy for triple-negative breast cancer / 中国肿瘤临床

Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is characterized by the lack of estro-gen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), thereby making it difficult to treat. Owing to the aggressive clinical behavior of TNBC and the lack of recognized molecular targets for therapy, patients with TNBC have shown poorer outcomes than those with other subtypes of breast cancer. Chemotherapy is the primary established systemic treatment for TNBC. However, various novel therapeutic targets have come into focus with the advances in molecular characterization of TNBC. In recent years, several targeted drugs have undergone clinical trials and have shown certain curative effects with relatively mild adverse reactions. The Food and Drug Administration has approved some of these drugs. In the current review, we have summa-rized the advances in the targeted therapy of TNBC.

Strategies of nano drug delivery system applied in anti-angiogenic therapy / 中国药科大学学报

@#Anti-angiogenic therapy has a wide range of applications in the treatment of tumor. Nano drug delivery system can contribute to higher efficacy and lower toxicity in anti-angiogenic therapy. This article reviews the application of nano drug delivery system in anti-angiogenic therapy and introduces the strategies to improve its treatment efficiency with varieties of nanoparticles, providing reference for the development of anti-angiogenic therapy.

Anti-angiogenic activity of iridoids from Galium tunetanum

ABSTRACT The phytochemical study of Galium tunetanum Lam., Rubiaceae, leaves led to the isolation of 13 compounds from the chloroform-methanol and the methanol extracts, including six iridoid glycosides, one non-glycoside iridoid, two p-coumaroyl iridoid glycosides, two phenolic acids, and two flavonoid glycosides. The structural determination of the isolated compounds was performed by mono- and bidimensional NMR spectroscopic data, as well as ESI-MS experiments. All compounds were isolated from this species for the first time. The anti-angiogenic effects of the isolated iridoids were also reported on new blood vessels formation using the chick embryo chorioallantoic membrane as in vivo model. Results showed that among the isolated iridoids tested at the dose of 2 µg/egg, asperuloside (1), geniposidic acid (2), and iridoid V1 (3) reduced microvessel formation of the chorioallantoic membrane on morphological observations using a stereomicroscope. The anti-angiogenic effects of the active compounds, expressed as percentages of inhibition versus control, were 67% (1), 59% (2), and 54% (3), respectively. In addition, the active compounds were able to inhibit angiogenesis in the chorioallantoic membrane assay, in a dose-dependent manner (0.5-2 µg/egg) as compared to the standard retinoic acid.

Estrategias en el tratamiento de la retinopatía diabética / Treatment strategies for diabetic retinopathy

Con este trabajo nos proponemos revisar las evidencias científicas relacionadas con el tratamiento de la retinopatía diabética. Para la investigación documental se examinaron los artículos de la temática indexados en las bases de datos Pubmed, Pubmed Central y Scielo, que correspondieron a los descriptores DeCs-MeSH: retinopatía diabética y tratamiento actual. La evaluación de los datos se realizó mediante el análisis de contenido de tipo directo. El progreso de la retinopatía diabética va desde los estados más benignos hasta los más severos cuando no se aplica una intervención médica apropiada. Es importante reconocer cada estado de la retinopatía diabética para que el tratamiento sea más efectivo. Varias décadas de estudios clínicos han proporcionado excelentes datos sobre el curso natural de la enfermedad y la estrategia de tratamiento que son efectivas en alrededor de un 90 por ciento para prevenir la pérdida visual severa(AU)

The purpose of the study was to present scientific evidence associated with the treatment of diabetic retinopathy. Document analysis was conducted based on examination of papers about the topic indexed in the databases PubMed, PubMed Central and SciELO, using the DeCs-MeSH terms 'diabetic retinopathy' and 'current treatment'. Data were evaluated with the method of direct content analysis. Diabetic retinopathy evolves from its most benign stages to the severest when appropriate medical action is not taken. It is important to identify each stage of diabetic retinopathy and apply the most effective treatment. Several decades of clinical studies have provided excellent data about the natural course of the disease, as well as about treatment strategies which are effective in around 90 percent of the cases to prevent severe visual loss(AU)

1-Methoxycarbony-β-carboline from Picrasma quassioides exerts anti-angiogenic properties in HUVECs in vitro and zebrafish embryos in vivo / 中国天然药物

Angiogenesis is a crucial process in the development of inflammatory diseases, including cancer, psoriasis and rheumatoid arthritis. Recently, several alkaloids from Picrasma quassioides had been screened for angiogenic activity in the zebrafish model, and the results indicated that 1-methoxycarbony-β-carboline (MCC) could effectively inhibit blood vessel formation. In this study, we further confirmed that MCC can inhibit, in a concentration-dependent manner, the viability, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, as well as the regenerative vascular outgrowth of zebrafish caudal fin in vivo. In the zebrafish xenograft assay, MCC inhibited the growth of tumor masses and the metastatic transplanted DU145 tumor cells. The proteome profile array of the MCC-treated HUVECs showed that MCC could down-regulate several angiogenesis-related self-secreted proteins, including ANG, EGF, bFGF, GRO, IGF-1, PLG and MMP-1. In addition, the expression of two key membrane receptor proteins in angiogenesis, TIE-2 and uPAR, were also down-regulated after MCC treatment. Taken together, these results shed light on the potential therapeutic application of MCC as a potent natural angiogenesis inhibitor via multiple molecular targets.

Inhibitory effect of Tum5 on angiogenic activity of human umbilical vein endothelial cells and corneal neovascularization induce by alkali burn in rats / 眼科新进展

Objective To investigate the inhibitory effects of Tum5 on the angiogenesis of human umbilical vein endothelial cells (HUVECs) and alkali-induced corneal neovascularization.Methods HUVECs in logarithmic growth phase were divided into 4 groups,cells with untreated as normal control group,cells with the infection of rAdGFP virus as rAd-GFP group,cells with the infection of rAd-Tum5 virus as rAd-Tum5 group,and cells with the infection of rAd-Tum5 virus followed by VEGF treatment as rAd-Tum5 + VEGF group.Then cell proliferation,migration,and tube formation of HUVECs were examined by CCK-8,Transwell and Matrigel assays,respectively.Sixty-four healthy male SD rats were randomly divided into 4 groups (n =16) by using random number table,and they were normal control group,alkali-burn group,alkali-burn + rAd-GFP group,and alkali-burn + rAd-Tum5 group.The alkali-burn rat model was then established except normal control group,and the normal control group received no treatment,whereas the alkali-burn,alkali-burn + rAd-GFP,and alkali-burn + rAd-Tum5 groups received subconjunctival injection of equal volumes of sterilized saline,rAd-GFP virus,and rAd-Tum5 virus,respectively following the alkaline burn.The relative area of corneal neovascularization and the number of infiltrating inflammatory cells were recorded on day 1,7,and 14 after injection.Results The CCK-8 assay showed that the proliferative rate of rAd-Tum5 group was lower than that of the normal control group and rAd-GFP group (both P ＜0.01),while rAd-Tum5 + VEGF group exhibited a significantly greater cell proliferative capability than rAd-Tum5 group (P =0.004).There were no statistical differences between rAd-Tum5 + VEGF group,normal control group and rAdGFP group (all P ＞ 0.05).Transwell assay showed the significantly lower number of migrating cells in the rAd-Tum5 group than those in the normal control group and rAdGFP group (both P ＜ 0.01).The number of migrating cells in rAd-Tum5 + VEGF group was higher than those in rAd-Tum5 group (P =0.000);however,the migration capacity had not been restored to normal level,and rAd-Tum5 + VEGF group had significant difference with normal control group and rAd-Tum5 group (both P ＜0.05).Matrigel assay showed that the number of meshes in rAd-Tum5 group was lower than that in the normal control group and rAd-GFP group (both P ＜0.01);while the number of meshes in rAd-Tum5 + VEGF group was significantly increased compared with rAd-Tum5 group(P =0.001).The density and number of corneal neovascularization increased gradually from day 1 to day 14 after alkali burn,while the relative neovascularization area in the alkali-burn + rAd-Tum5 group was significantly reduced as compared to those in the alkali-burn group and alkali-burn + rAd-GFP group on day 7 and day 14,suggesting that Tum5 could reduce the growth rate and density of corneal neovascularization,so as to inhibit corneal neovascularization induced by alkali burn.On day 7 and 14 after alkali burn,in the normal control group,the corneas were intact,no infiltrating inflammatory cells and cells were arranged in an orderly manner.On day 7 after alkali burn,there were disordered epithelial structure,corneal edema and infiltrating inflammatory cells in alkali-burn group and alkali-burn + rAd-GFP group.The number of infiltrating inflammatory cells in alkaliburn + rAd-Tum5 group was significantly lower than that in alkali-burn group and alkali-burn + rAd-GFP group (both P ＜0.01).On day 14 after alkali burn,the number of infiltrating inflammatory cells in alkali-bum,alkali-burn + rAd-GFP and alkali-burn + rAd-Tum5 group were significantly lower than those on day 7,while the corneal epitheliums were intact and dropsy was alleviated,while the number of inflammatory cells was significantly lower than that in alkali burn group and alkali-burn + rAd-GFP group,with significant difference (both P ＜ 0.01).Conelusion Tum5 can inhibit the angiogenic capability of HUVECs by VEGF pathway,as well as suppress the alkali-burn-induced corneal neovascularization and inflammatory cell infiltration in rats.

¹⁸FFET PET is a useful tool for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic glioblastoma mouse model / 한국실험동물학회지

O-2-¹⁸F-fluoroethyl-l-tyrosine ([¹⁸F]FET) has been widely used for glioblastomas (GBM) in clinical practice, although evaluation of its applicability in non-clinical research is still lacking. The objective of this study was to examine the value of [¹⁸F]FET for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic mouse model of GBM. Human U87MG cells were implanted into nude mice and then bevacizumab, a representative anti-angiogenic drug, was administered. We monitored the effect of anti-angiogenic agents using multiple imaging modalities, including bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT). Among these imaging methods analyzed, only [¹⁸F]FET uptake showed a statistically significant decrease in the treatment group compared to the control group (P=0.02 and P=0.03 at 5 and 20 mg/kg, respectively). This indicates that [¹⁸F]FET PET is a sensitive method to monitor the response of GBM bearing mice to anti-angiogenic drug. Moreover, [¹⁸F]FET uptake was confirmed to be a significant parameter for predicting the prognosis of anti-angiogenic drug (P=0.041 and P=0.007, on Days 7 and 12, respectively, on Pearson's correlation; P=0.048 and P=0.030, on Days 7 and 12, respectively, on Cox regression analysis). However, results of BLI or MRI were not significantly associated with survival time. In conclusion, this study suggests that [¹⁸F]FET PET imaging is a pertinent imaging modality for sensitive monitoring and accurate prediction of treatment response to anti-angiogenic agents in an orthotopic model of GBM.

1-Methoxycarbony-β-carboline from Picrasma quassioides exerts anti-angiogenic properties in HUVECs in vitro and zebrafish embryos in vivo / 中国天然药物

Angiogenesis is a crucial process in the development of inflammatory diseases, including cancer, psoriasis and rheumatoid arthritis. Recently, several alkaloids from Picrasma quassioides had been screened for angiogenic activity in the zebrafish model, and the results indicated that 1-methoxycarbony-β-carboline (MCC) could effectively inhibit blood vessel formation. In this study, we further confirmed that MCC can inhibit, in a concentration-dependent manner, the viability, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, as well as the regenerative vascular outgrowth of zebrafish caudal fin in vivo. In the zebrafish xenograft assay, MCC inhibited the growth of tumor masses and the metastatic transplanted DU145 tumor cells. The proteome profile array of the MCC-treated HUVECs showed that MCC could down-regulate several angiogenesis-related self-secreted proteins, including ANG, EGF, bFGF, GRO, IGF-1, PLG and MMP-1. In addition, the expression of two key membrane receptor proteins in angiogenesis, TIE-2 and uPAR, were also down-regulated after MCC treatment. Taken together, these results shed light on the potential therapeutic application of MCC as a potent natural angiogenesis inhibitor via multiple molecular targets.

Anti-angiogenic therapy for gallbladder carcinoma using contrast enhanced ultrasound / 中华肝胆外科杂志

Objective To evaluate the feasibility of contrast enhanced ultrasound (CEUS) in gallbladder carcinoma anti-angiogenesis treatment.Methods Subcutaneous gallbladder carcinoma model was consturcted.The mice were divided into intervention-drug group and control group randomly.The mice of intervention-drug group were treated with Endostar (10 mg · kg-1 · d-1) by intraperitoneal injection for two weeks.Two groups of mice were detected by CEUS,then the time of arrival (AT),peak time (TTP),peak intensity (PI),area under the curve (AUC) were measured via time-intensity curve.Expression of MVD and VEGF both in the intervention and control groups were studied through immunohistochemistry.and the correlations between MVD,VEGF and CEUS parameteres were further analyzed.Results The mean values of PI in drug intervention group and control group were 10.8 ± 5.5 and 16.8 ± 5.8,respectively.The values of PI in intervention-drug group were lower than that in control group significantly (P ＜ 0.05).There was no significant difference in AT,TTP,AUC between the two groups.The mean values of MVD on drug intervention group and control group were 8.5 ± 3.8 and 13.1 ± 3.5,respectively.The mean values of VEGF on drug intervention group and control group were 4.3 ± 0.5 and 4.7 ± 0.4,respectively.The values of MVD and VEGF in intervention-drug group were significant lower than that control group (P ＜ 0.05).MVD and VEGF values of intervention-drug group were correlated with PI (r =0.712,P ＜ 0.05;r =0.739,P ＜ 0.05).Conclusion Endostar can inhibit the growth of gallbladder carcinoma and PI can be used as an effective marker to evaluatethe effect of anti-angiogenic therapy in gallbladder carcinoma.