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.

The key mechanism underlying resistance to anti-angiogenic therapy in liver cancer: vessel co-option / 中华消化外科杂志

The growth of solid tumors rely on angiogenesis to establish blood supply, and inducing neovascularization is a necessary condition for the growth of solid tumors. Anti-angiogenic therapies have been developed for tumors based on this theory. Although liver cancer is considered as a highly angiogenic tumor, the effectiveness of these drugs in anti-angiogenic therapies on liver cancer has not met expectations. In recent years, vessel co-option, as a long-standing but overlooked mechanism of vascularization of non-angiogenic tumors, has gradually attracted attention. Tumor tissue can promote its own growth by "hijacking" existing blood vessels in the para-carcinoma tissue instead of inducing angiogenesis, known as vessel co-option or vascular hijacking. Vessel co-option has been observed in a variety of tumors, both primary and metastatic, and is believed to be a key mechanism of anti-angiogenic resistance. The authors systematically examine the evidence, clinical prognosis, and molecular mechanisms of vessel co-option in liver cancer, and discuss its potential role in anti-angiogenic therapeutic resistance and alternative anti-tumor strategies for liver cancer.

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.

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 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.

Mechanisms of tumor invasion metastasis caused by long-term anti-angiogenic therapy / 中国肿瘤临床

Hypoxia results from long-term anti-angiogenic therapy and can stimulate hypoxia-inducible factors (HIFs). HIF-induced hy-poxia signaling is involved in various steps in tumor invasive-metastatic cascade. On the one hand, HIFs regulate epithelial-mesenchy-mal transition. On the other hand, the characteristics of pericytes around vessels and the links among endothelial cells can change;thus, tumor cells can more easily intravasate into blood vessels, survive in peripheral blood, and then reach specific organs, ultimately resulting in metastasis. This review discusses the emerging mechanisms of long-term anti-angiogenic therapy and the occurrence of metastasis.

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.

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.

Perfusion computed tomography permits the assessment of non-small-cell lung cancer treated with anti-angiogenic therapy / 中国肿瘤临床

As a non-invasive functional radiographic imaging method, perfusion computed tomography (PCT) permits the evalu-ation of non-small-cell lung cancer (NSCLC) angiogenesis and response to therapy by demonstrating alterations in NSCLC vascularity. PCT performed shortly after initiating therapy may provide a better evaluation of physiological changes rather than conventional size as-sessment obtained by response evaluation criteria in solid tumors. Based on the angiogenesis principle of NSCLC, the main evaluation indexes of PCT are blood flow, blood volume, mean transit time, permeability surface, and peak enhancement index. The relationship between PCT and the indexes of vascular normalization may have implications for exploring the predictive model of efficacy and prognostic factors of NSCLC. The cavity of microvessel in NSCLC and expression of VEGF factors are closely related to PCT imag-ing. According to PCT assessment, pathological classification and histological type of NSCLC play significant roles. However, techni-cal limitations, reproducibility of blood flow parameters, radiation dose, and volume of contrast medium delivered to the patient are some issues in this type of investigation. With the development of PCT technology and anti-angiogenesis drugs for NSCLC, more mo-lecular imaging markers and standardized targeted therapies will be available. Such advancements will provide a wider space for the as-sessment of NSCLC treated with anti-angiogenic therapy using PCT.

Prognostic and predictive biomarkers of anti-angiogenic therapy for non-small cell lung cancer / 中国肿瘤临床

Non-small cell lung cancer (NSCLC) is currently the leading cause of cancer-related deaths worldwide. Angiogenesis, the formation of new vasculature, is a complex and strictly regulated process that promotes metastasis and disease progression in lung cancer and other malignancies. Anti-angiogenic therapy is an anti-cancer strategy that targets the new vessels. Most anti-cancer agents used in the clinic include cytotoxic drugs, which target all rapidly dividing cells, resulting in severe adverse effects. These effects in-clude immunosuppression, intestinal problems, and hair loss. By contrast, anti-angiogenic agents theoretically exhibit fewer side effects because angiogenesis rarely occurs in healthy adults, except in the uterine endometrium. Various angiogenic factors may contribute to the regulation of angiogenesis in the individual tumor;thus, the proper selection of patients who may benefit from a specific therapy is important, considering the increasing number of clinically tested agents. This study provides an overview of angiogenic molecules cur-rently being investigated as prognostic and predictive biomarkers in NSCLC. Clinical examples are presented to show the rationales for investigating various biomarkers of pre-clinical studies.

The combination of intravenous bevacizumab and metronomic oral cyclophosphamide is an effective regimen for platinum-resistant recurrent ovarian cancer / 부인종양

OBJECTIVE: To determine the efficacy, progression-free survival (PFS) and overall survival (OS) for the combination of intravenous bevacizumab and oral cyclophosphamide in heavily pretreated patients with recurrent ovarian carcinoma. METHODS: A retrospective review was performed for all patients with recurrent ovarian carcinoma treated with intravenous bevacizumab 10 mg/kg every 14 days and oral cyclophosphamide 50 mg daily between January 2006 and December 2010. Response to treatment was determined by Response Evaluation Criteria in Solid Tumors criteria and/or CA-125 levels. RESULTS: Sixty-six eligible patients were identified. Median age was 53 years. Fifty-five patients (83%) had undergone optimal cytoreduction. All patients were primarily or secondarily platinum resistant at the time of administration of bevacizumab and cyclophosphamide. The median number of prior chemotherapy treatments was 6.5 (range, 3 to 16). Eight patients (12.1%) had side effects which required discontinuation of bevacizumab and cyclophosphamide. There was one bowel perforation (1.5%). Overall response rate was 42.4%, including, complete response in 7 patients (10.6%), and partial response in 21 patients (31.8%), while 15 patients (22.7%) had stable disease and 23 patients (34.8%) had disease progression. Median PFS for responders was 5 months (range, 2 to 14 months). Median OS from initiation of bevacizumab and cyclophosphamide was 20 months (range, 2 to 56 months) for responders and 9 months (range, 2 to 51 months) for non-responders (p=0.004). CONCLUSION: Bevacizumab and cyclophosphamide is an effective, well-tolerated chemotherapy regimen in heavily pretreated patients with recurrent ovarian carcinoma. This combination significantly improved PFS and OS in responders. Response rates were similar and favorable to the rates reported for similar patients receiving other commonly used second-line chemotherapeutic agents.

A novel VEGF16S-PE38 fusion gene for anti-angiogenic therapy in malignant glioma of nude mice model / 中华神经医学杂志

Objective To evaluate the anti-angiogenic effect of eukaryotic vector containing human VEGF 165 and truncated pseudomonas exotoxin A (PE38) fusion gene on malignant glioma in nude mice, and explore a novel anti-angiogenic therapy for cancer. Methods The models were established through hypodermic injection of human U251 glioma cells into the nude mice and randomly divided into untreated group, PBS group, pIRES2-EGFP group and pIRES2-VEGF165-PE38-EGFP group on the 9th day. H&E staining was performed to observe the morphological changes of the glioma tissues; SP immunohistochemistry was employed to detect the expression of GFAP, CD31 andPE; quantitative pathologic image analysis system was used to investigate the microvessel density (MVD) in the tumor tissues. Results At day 16, the pIRES2-VEGF165PE38-EGFP group showed significantly lower tumor volume of mice and significantly decreased MVD than the other three groups (P<0.05). Positive expression of PE was shown in the pIRES2-VEGF165PE38-EGFP group, but negative in the other three groups. Conclusion The expression products of VEGFJ65-PE38 fusion gene can obviously inhibit the growth and angiogenesis of U2S1 cells in nude mouse flank tumor models, suggesting that it may be a novel therapeutic approach for anti-angiogenic therapy of cancer.

Terapia antiangiogénica ocular: experiencia clínica en México / Mexican clinical experience in ocular anti-angiogenic therapy

La angiogénesis patológica retiniana es la causa principal de pérdida visual en una gran cantidad de enfermedades: degeneración macular relacionada a la edad, retinopatía diabética y retinopatía del prematuro, en otras. Estas últimas dos son, además, problemas de salud pública en los países en desarrollo. Estudios recientes sobre la fisiopatología de estas enfermedades han demostrado el papel fundamental que los factores de crecimiento tienen sobre la angiogénesis. La terapia antiangiogénica ocular nació como un esfuerzo de inhibir la acción de estos factores sobre la angiogénesis patológica y preservar la visión. El objetivo de esta revisión es hacer un recuento de la experiencia en México en cuanto a esta modalidad terapéutica.

Retinal pathological angiogenesis is the leading cause of visual loss in a wide variety of ocular diseases. Some of the examples include: Age-related macular degeneration, diabetic retinopathy and retinopathy associated with prematurity. These last two entities are, in addition, public health problems in developing countries. Recent physiopathological studies, have demonstrated that growth factors play a key role on angiogenesis. Anti-angiogenic therapy came about as an attempt to inhibit the action of growth factors over the process of pathological angiogenesis in order to preserve vision. The objective of this review is to describe Mexico's experience using this therapeutic approach.

The characteristics and treating strategy on the micro-environment of solid tumor / 医学研究生学报

The occurrence and development of solid tumor is a multi-factor,multi-step and multi-gene interactive process.The generation of micro vasculature of solid tumor,as well as the interaction between tumor and micro-environment,decides the tumor's biological characteristics of growth,recurrence,invasion and metastasis.Reasonable application of anti-angiogenesis therapy enables the normalization of tumor vascular system to enhance the efficiency of chemotherapy and radiation treatment and prolong survival time in patients.

Angiogenesis research and its progresses in the field of hepatocellular carcinoma / 中国癌症杂志

Purpose:Tumor growth and metastasis depend on angiogenesis, which is regulated by stimulating and inhibitory factors. Evaluation of angiogenesis of tumor is of value in predicting prognosis, and anti angiogenic therapy is a promising treatment of cancer. Genetic bases for angiogenesis control and search for new angiogenesis inhibitory factors remain to be studied in the future. Studies on relationship between angiogenic factors, such as vascular endothelial growth factors and basic fibroblast growth factors, and angiogenesis induced by hepatocellular carcinoma(HCC) are summarized in this paper. Experimental studies imply that anti angiogenic therapy will become a new modality in the treatment of HCC.

Advancement of breast cancer and angiogenesis / 中国癌症杂志

Angiogensis plays an important role in tumor growth and metastasis,and anti-angiogenic therapy is a promising treatment of cancer. We review the proceedings on angiogensis and breast cancer ,and the progress in the field of anti-angiogenic therapy for breast cancer.