Recombinant Human Endostatin Research Articles

Mechanism and Functional Parameter of Myocardial Damage Induced by Low-Dose Radiation in Rats

Radiation induced heart damage (RIHD) is the leading cause of non-cancer-related deaths in patients receiving thoracic radiotherapy. The mean cardiac dose (MHD) of normal tissue tolerance in NCCN guidelines for radiotherapy has been continuously decreased from 35 Gy in 2017 to 2020 20 Gy, indicating there is controversy of MHD that how much dose could control cardiac radiation damage better. In this study, 15 Gy/3f (BED = 40 Gy) low-dose irradiation of SD rat heart was used to explore the mechanism and functional parameter changes of RIDH caused by low-dose irradiation, and to explore the effect of combining recombinant human endostatin (E).75 SD adult male rats were randomly divided into control group (C, E, MHD25) and experimental group (MHD15, MHD15+E). A single dose 5 Gy/f, once per day, continuous irradiation 3d or 5d. After the irradiation, the E group and MHD15+E group were given recombinant human endostatin 6mg/kg intraperitoneal injection, once per day, for 14 consecutive days. At 24h, 48h and 15d after the intervention, the blood of the rats was taken to measure CK, CK-MB, LDH and CRP. At 1, 3 and 6 months, 5 rats after cardiac echocardiography was performed in each group were randomly killed and myocardial tissues were collected for Masson staining, Western Blot and qPCR. Two-way ANOVA statistics.There was no difference in LDH, CK, CK-MB, and CRP in the same time period among the groups at 24h, 48h, and 14d after intervention (P > 0. 05). Compared with group C, the EF and FS of the MHD25, MHD15 and MHD15+E group all decreased at 3 months (P < 0.05), and the degree was similar (P > 0.05). The EF and FS of the MHD25, MHD15 and MHD15+E group also decreased at 6 months (P < 0.05), and the degree was similar (P > 0.05). Comparing 6 months with 1 month, EF and FS of each group decreased (P < 0.01). Myocardial fibrosis MHD25 group appeared after 3 months of irradiation. Myocardial collagen volume fraction (CVF) increased (P < 0.05), and TGF-β1, P-smad2, Collagen-I protein expression increased (P < 0.05), and TGF-β1, Smad, Collagen-I gene expression increased (P < 0.05). The MHD15 and MHD15+E group showed the above changes at 6 months, and the degree of increase of the above-mentioned protein and gene expression was lower than that of the MHD25 group (P < 0.05). The expressions of the above-mentioned proteins and genes in the MHD15+E group were higher than those in the MHD15 group (P < 0.05). The protein level of Smad2 was similar in each group (P > 0.05).SD rat heart 15 Gy/3f (BED = 40 Gy) low-dose irradiation cause cardiac function damage in the early stage and myocardial fibrosis in the late stage, the appearance delayed and degree is lower than that of high-dose irradiation. On the basis of low-dose irradiation, combined with recombinant human endostatin increase the expression of related factors of TGF-β/Smad signaling pathway. Echocardiography may be able to predict the occurrence of RIDH early, but serological predictive indicators have yet to be found.

Recombinant Human Endostatin Combined With Radiation Promotes Myocardial Fibrosis in Rat via TGF-β1/Smads/CTGF Signaling Pathway

Recombinant human endostatin (rh-ES) has been found to cause heart damage in clinical use. The heart tissue can be irradiated inevitably while radiation therapy for chest tumors and may result in radiation damage. The regulation of myocardial fibrosis may be related to TGF-β1, Smad2/3, and CTGF signaling pathways. At present, whether targeted drug therapy combined with radiotherapy will increase the damage of the heart is a subject worth studying.The experimental animals were randomly divided into 25 Gy irradiation group (5 Gy/ time × 5 days), rh-ES 6mg/kg group, rh-ES 12mg/kg group, 25 Gy irradiation + rh-ES 6mg/kg group, 25 Gy irradiation + rh-ES 12mg/kg group and blank control group, with 15 in each group. rh-ES was injected intraperitoneally for 14 consecutive days. Five rats in each group were sacrificed and the cardiac tissues were extracted for HE staining, Masson staining and transmission electron microscopy at 1, 3 and 6 months after irradiation and rh-ES rejection. MTT was used to detect the value of the IC50 rh-ES to cardiomyocytes with different concentrations of rh-ES. The cardiomyocytes with stable knockdown of TGF-β1 is grouped, the irradiation dose is 10 Gy. According to cardiomyocytes trial were divided into four group, the blank control group (without any treatment), the irradiation group (irradiation + TGF-β1 gene knockdown), the rh-ES group (rh-ES + TGF-β1 gene knockdown), the combined group (irradiation, rh-ES and TGF-β1 gene knockdown), flow cytometry was used to detect cardiomyocytes apoptosis, qPCR and Western Blot were used to detect the expression of TGF-β1/Smad2. Smad3/CTGF gene and protein.In vivo experiments on the heart of rats showed that a little inflammatory cell infiltration was observed under light microscope at 1 month after radiation and rh-ES treatment, and the inflammatory cell infiltration was obvious with fibrosis changes at 3 months, and the fibrosis changes were aggravated 6 months later. rh-ES alone caused slight injury to rats (no change under light microscope, but some mitochondria swelling and cristae missing under electron microscope). rh-ES and radiation treatment increased the damage of myocardial tissues in rats to some extent, and the process of radiation-induced myocardial fibrosis lasted at least 6 months after radiotherapy. rh-ES can aggravate the process of myocardial fibrosis after radiation injury, but has no toxic effect on normal myocardial tissue. The IC50 value of rh-ES on rat cardiomyocytes was 529μg/ mL in vitro experiment. qPCR and Western Blot results showed that TGF-β1, Smad2/Smad3, CTGF gene and protein expressions were up-regulated in rat cardiomyocytes after rh-ES and irradiation treatment.The TGF-β1, Smad2/Smad3 and CTGF signaling pathways may be the common signaling pathways of myocardial fibrosis injury induced by rh-ES combined with radiation, which may be the target for the treatment of myocardial fibrosis by radiation.

Study on Damage of Myocardial Tissue Under Low-Dose Heart Irradiation in Rats

<h3>Purpose/Objective(s)</h3> Radiation induced heart damage (RIHD) is an important late toxicity of thoracic radiotherapy, which is closely relating with the fractional dose of radiotherapy. With the wide application of stereotactic body radiotherapy and hyperfractionated radiotherapy, the single dose and biological equivalent dose (BED) of the heart of exposure have increased when comparing with conventionally fractionated radiotherapy. However, the mean cardiac dose (MHD), which is frequently used clinically to ensure the control of cardiac damage, is continuously decreased to 26 Gy, 20 Gy, etc. There is still controversy about how much dose could control heart radiation damage better. In this study, 15 Gy/3f low-dose irradiation of the whole heart of rats, which BED is similar with 24 Gy/12f irradiation, is selected to explore the possibility and characteristics of RIHD occurrence, and explore the effect of combined recombinant human endostatin on myocardial damage. <h3>Materials/Methods</h3> 75 SD adult male rats were randomly divided into control (C group, E group, MHD₂₅ group) and experimental group (MHD₁₅ group, MHD_15+E group). The irradiation method was single dose 5 Gy/f, once per day, continuous irradiation 3d or 5d. After the irradiation, the E group and MHD_15+E group were given recombinant human endostatin 6mg/kg intraperitoneal injection, once per day, for 14 consecutive days. At 1, 3, and 6 months after intervention, 5 rats in each group were randomly selected for HE, Masson, and immunohistochemical CD34 microvessel staining, and Western Blot detected mitochondrial Complex II protein expression. Two-way ANOVA statistics. <h3>Results</h3> Compared with C group, edema and disorder of myocardial cells, infiltration of inflammatory cells and decrease of microvessel density was observed at 1 month after intervention in HE staining in MHD₁₅ and MHD_15+E group. The expression of complex II protein decreased at 6 months, and the degree of decrease was less than that in MHD₂₅ group (positive control group) (<i>P</i> < 0.05). The microvessel density was further decreased compared with 1 month. Myocardial fibrosis induced by 15 Gy/3f low-dose irradiation of SD rat heart mainly occurred at 6 months, which observed myocardial cord or reticular fibrosis and collagen deposition. Semi-quantitative analysis of myocardial collagen volume fraction CVF significantly increased (<i>P</i> < 0.001) in HE and Masson staining. Details is shown in the table below. Compared with C group, E group observed myocardial edema and decreased microvessel density. There was no significant difference between MHD₁₅ and MHD_15+E group. <h3>Conclusion</h3> Low dose irradiation of 15 Gy/3f (BED = 40 Gy) still cause myocardial fibrosis and damage of cardiac function in SD rats. RIHD were observed after 6 months, which was equal to about 1/5 of the rat's life span, and the time was delayed when compared with the time of RIHD caused by high dose irradiation. Cardiotoxicity was not increased significantly combining recombinant human endostatin on the basis of low-dose cardiac.

P40.14 Efficacy and Safety of Endostar Combined With Camrelizumab and Chemotherapy in Treatment of Advanced NSCLC: A Multi-Center Retrospective Study

Both Recombinant human endostatin (Endostar) and Camrelizumab have been approved in combination with chemotherapy in treatment of NSCLC in China. This study aims to observe the efficacy and safety of endostar plus Camrelizumab and chemotherapy in treatment of advanced NSCLC. This is periodic result. This is a multi-center, retrospective study. Advanced NSCLC patients (pts) who received endostar plus Camrelizumab and chemotherapy at least 2 courses were collected from December 2019. After two courses, the follow-up therapy will be decided by investigators. Baseline characteristics, efficacy evaluation and safety data were analyzed. Tumor response was evaluated according to RECIST 1.1. Adverse events (AEs) were graded according to NCI-CTC AE 4.0. The primary endpoint was progress-free survival (PFS), overall response rate (ORR), duration of response (DOR), overall survival (OS) and safety were included among secondary endpoint. Untill Mar. 2021, 21 pts were enrolled, and 17 pts were analyzed. The median age of pts was 55 years. 71% was male, 90% was diagnosed at stage IV. 76% was adenocarcinoma and 19% was squamous cell carcinoma. 67% received endostar combined with Camrelizumab and chemotherapy as first-line. The ORR and DCR is 71% and 100% respectively, with one CR patient. The treatment of 52% (11) pts is ongoing and the median PFS was not reach. In the safety-evaluable population, the most common AEs is thrombocytopenia (24%，>3 grade 10%), nausea and vomiting(24%，>3 grade 5%) and liver damage (19%). One pt was considered as immune-related hepatitis. Reactive cutaneous capillary endothelial proliferation (RCCEP) caused by Camrelizumab is 10% and none in >3 grade AEs.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This retrospective study showed a promising efficacy and a good tolerance in advanced NSCLC pts with Endostar plus Camrelizumab and chemotherapy. This combined treatment maybe a new choice and we look forward to prospective study in furture.

780P Safety and efficacy of endostar combined with platinum-based chemotherapy in the first-line treatment of recurrence and metastatic cervical cancer: A single-arm, prospective phase II study

Endostar (a recombinant human endostatin), as a anti-angiogenesis agent, combined with chemotherapy is well-tolerated in patients with metastatic colorectal cancer, gastric cancer and advanced non-small cell lung cancer, but fewer reports are on cervical cancer. Safety and efficacy of endostar combined with platinum-based regimens in the first-line treatment of recurrence and metastatic cervical cancer remains unknown.

Clinical Study of Recombinant Human Endostatin Combined with Iressa in Targeted Treatment of Patients with Lung Adenocarcinoma with Pleural Metastasis

Objective: To evaluate and comprehensively analyze the clinical efficacy of recombinant human endostatin combined with Iressa targeted therapy in patients with pleural metastasis of lung adenocarcinoma. Methods: The interval of the selected study period span was from January 2017 to April 2021. The sample source of the study was 42 patients with lung adenocarcinoma admitted to hospital. The random number table method was used for study grouping, and they were further divided into study groups (n = 21, 14 cases with pleural metastasis) and control group (n=21, 13 cases with pleural metastasis), all patients received systemic chemotherapy with pemetrexed and cisplatin. Patients with pleural metastases in the control group were injected with 60 mg cisplatin into the thoracic cavity. Patients in the study group were treated with Iressa (gefitinib) targeted therapy if genetic testing showed epidermal growth factor receptor (EGRF) mutations, and patients with pleural metastases were treated with pleural metastasis with Endo (recombinant human endostatin YH-16) to control pleural effusion. Two sets of related indicators were compared and analyzed. Results: Comparing the short-term disease control rate, treatment effectiveness and long-term survival rate between the two groups shows that the study group has more advantages (P&lt;0.05). In the comparison between the two groups of serum markers and related indicators, the study group has more advantages (P&lt;0.05), whereas in the comparison between the two groups in the incidence of adverse reactions, there is no significant difference (P&gt;0.05). Based on statistics of the recurrence rate of pleural fluid in the two groups, the study group is significantly lower than the control group (P&lt;0.05). Conclusion: Recombinant human endostatin combined with Iressa targeted therapy for patients with lung adenocarcinoma with pleural metastasis has significant short-term and long-term effects without serious adverse reactions. It can be fully promoted in medical institutions at all levels.

Current research progress in targeted anti-angiogenesis therapy for osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone tumour with a peak in incidence during adolescence. Delayed patient presentation and diagnosis is common with approximately 15% of OS patients presenting with metastatic disease at initial diagnosis. With the introduction of neoadjuvant chemotherapy in the 1970s, disease prognosis improved from 17% to 60%‐70% 5‐year survival, but outcomes have not significantly improved since then. Novel and innovative therapeutic strategies are urgently needed as an adjunct to conventional treatment modalities to improve outcomes for OS patients. Angiogenesis is crucial for tumour growth, metastasis and invasion, and its prevention will ultimately inhibit tumour growth and metastasis. Dysregulation of angiogenesis in bone microenvironment involving osteoblasts and osteoclasts might contribute to OS development. This review summarizes existing knowledge regarding pre‐clinical and developmental research of targeted anti‐angiogenic therapy for OS with the aim of highlighting the limitations associated with this application. Targeted anti‐angiogenic therapies include monoclonal antibody to VEGF (bevacizumab), tyrosine kinase inhibitors (Sorafenib, Apatinib, Pazopanib and Regorafenib) and human recombinant endostatin (Endostar). However, considering the safety and efficacy of these targeted anti‐angiogenesis therapies in clinical trials cannot be guaranteed at this point, further research is needed to completely understand and characterize targeted anti‐angiogenesis therapy in OS.

Systematic evaluation Meta-analysis of the efficacy of recombinant human endostatin combined with gemcitabine and cisplatin in non-small cell lung cancer

Systematic evaluation Meta-analysis of the efficacy of recombinant human endostatin combined with gemcitabine and cisplatin in non-small cell lung cancer

Recombinant human vascular endostatin injection to synchronize craniospinal radiotherapy for the treatment of recurrent medulloblastoma in children: A retrospective clinical study*

Abstract Objective Medulloblastoma (MB) is the most common primary central nervous system malignancy in children. Nonetheless, there is no standard treatment for recurrent MB. The purpose of this study was to investigate the clinical value and toxicity of recombinant human endostatin injection (Endostar®) combined with craniospinal radiotherapy for the treatment of recurrent MB in children. Methods This study retrospectively analyzed 13 patients with recurrent MB aged 5-18 years. Endostar® 7.5 mg/m2/d was synchronized during craniospinal radiotherapy for 7 children with a portable micro uniform speed infusion pump. Endostar® was applied 3 days prior to the initiation of radiotherapy. The drug was in continuous use for 7 days. Similarly, the withdrawal of the drug took place over 7 days. This represented a cycle. During radiotherapy, the application was repeated until the end of radiotherapy (experimental group). In the other 6 cases, only craniospinal radiotherapy was used (control group). Results The complete remission rate was 71.4% in the experimental group and 16.7% in the control group. The median progression-free survival (PFS) was 14 months (95% CI: 0.0-29.60) and 19 months (95% CI: 0.0-39.53) in the experimental and control groups, respectively. The median overall survival (OS) was 19 months (95% CI: 0.0-38.20) and 23 months (95% CI: 2.47-43.53) in the experimental and control groups, respectively. The most common adverse events included grade 1 thrombocytopenia (7.7%), grade 3 neutropenia (38.5%), and grade 1 anemia (30.8%). Conclusion Endostar® synchronizing craniospinal radiotherapy significantly improved the complete response rate of children with recurrent MB. It did not increase the side effects of radiation therapy. However, it did not improve the PFS or OS.

Safety and efficacy of nivolumab plus recombinant human endostatin in previously treated advanced non-small cell lung cancer: A prospective and multicenter phase 2 trial.

e21079 Background: Although the administration of immune checkpoint inhibitors (ICIs) and antiangiogenic agents in advanced non–small-cell lung cancer (NSCLC) has been well established, evidence supporting the combination of immune checkpoint inhibitors plus antiangiogenic drugs in previous treatment patients with advanced NSCLC is insufficient. We aimed to investigate the efficacy and safety of nivolumab combined with recombinant human endostatin (rh-Endostatin) as second-line or later treatment for advanced NSCLC. Methods: In this prospective and multicentre phase 2 trial we enrolled patients with advanced NSCLC who had not responded to standardized first-line treatment regimen from two cancer centres in China. Eligible patients were those aged 18-75 years without ICIs in first-line treatment who received nivolumab (3mg/kg, intravenous drip, day 1) every 2 weeks and rh-Endostatin (30 mg, 24-hour continous intravenous infusion，day 1–7) every 4 weeks till disease progression or discontinuation. The primary end points were objective response rate and safety. This study is registered with Chinese Clinical Trial Registry, number ChiCTR1900023664. Results: A total of 35 patients (median age, 60 years; range, 37-72 years) received nivolumab and rh-Endostatin. Median previous treated line of eligible patients was 2 lines (range, 1-7 lines). Patients received a median of 2 cycles of therapy (range, 1-14 cycles). Eleven of 33 evaluable patients achieved confirmed partial response with an objective response rate of 33.3% (11/33, 95% confidence interval [CI]: 17.2% – 49.4%) and disease control rate of 60.6% (20/33,95%CI:43.9%–77.3%). Median follow-up was 8.2 months (range: 0.9 –17.1). Median progression-free survival was 7.1 months (95% CI: 1.2m–13.0m), median overall survival was not reached and the 6-month overall survival rate was 54.5% (95% CI:37.6%–71.4%). The predominant grade 1-2 adverse events were thyroiditis, arrhythmia, hypertension. The grade 3 treatment-related adverse events were pneumonitis (3/35, 8.6%), hypertension (1/35, 2.9%) and atrial fibrillation (1/35, 2.9%), respectively. No grade 4 or 5 treatment-related adverse events were observed. Conclusions: To the best of our knowledge, this is the first prospective study that assessed nivolumab combined with rh-Endostatin as second-line or later treatment in pretreated patients with advanced NSCLC. In view of its encouraging efficacy and safety profile, nivolumab plus rh-Endostatin represents a promising treatment regimen in this patient population. Clinical trial information: ChiCTR1900023664.

Platinum-based chemotherapy combined with endostar in the treatment of advanced NSCLC: A real world study.

e21033 Background: Recombinant human endostatin (endostar), an angiogenesis inhibitor, has been approved for the treatment of NSCLC in combination with chemotherapy in China. This study aims to evaluate real world efficacy and safety of endostar combined with platinum-based chemotherapy in the treatment of advanced NSCLC. Methods: This study retrospectively collected electronic medical record system (EMR) information of NSCLC patients (pts) who received endostar combined with platinum-based chemotherapy regiments from June 2012 to August 2019 in 7 cancer hospitals after obtaining ethical approval. Baseline characteristics, efficacy evaluation and safety data were analyzed. Tumor response was evaluated according to RECIST 1.1. Adverse events (AEs) were graded according to NCI-CTC AE 4.0. The endpoints include objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: 512 advanced NSCLC pts who received endostar combined with platinum-based chemotherapy regiments were analyzed. The median age of pts was 59.2 years. Most pts were male, accounting for 75.2%. 63.3% pts was diagnosed at stage IV. 40.0% pts was adenocarcinoma and 35.4% pts was squamous cell carcinoma. 81.4% pts received endostar combined with chemotherapy as first-line. 292 people were included in the efficacy analysis set. The ORR, DCR and median PFS were 34%, 73% and 8.2 (95% CI 6.0-13.7) months, respectively. There were no significant differences of ORR and DCR among common platinum-based chemotherapy. The most common AEs were gastrointestinal reactions (29%), bone marrow suppression (14%), and liver damage (12%). Conclusions: The real-world data confirmed the superiority of endostar plus platinum-based chemotherapy in Chinese advanced NSCLC pts, with acceptable adverse effects. Clinical trial information: ChiCTR2000035129.

Recombinant human endostatin combined with chemotherapy for advanced squamous cell lung cancer: a meta-analysis

BackgroundThis paper aims to compare the efficacy and safety of recombinant human endostatin combined with chemotherapy in patients with squamous cell lung cancer (SqCLC).MethodsWe searched the Cochrane Library, PubMed, Embase, CNKI, Wanfang database, Metstr, VIP, and others and manually searched books and magazines until 2019 for articles about the efficacy and safety of recombinant human endostatin combined with chemotherapy in patients with SqCLC. A second search was conducted on the review literature. According to the criteria of the literature screen, the relevant randomized controlled trials (RCTs) and nonrandomized controlled trials (non-RCTs) of recombinant human endostatin combined with chemotherapy and chemotherapy alone in the treatment of SqCLC were included. After the data were extracted and analyzed, RevMan 5.3 software was used for meta-analysis for the outcome indicators. Then, heterogeneity tests and sensitivity analyses were carried out, and the publication bias of this study was tested in Stata 13.0 software. Six RCTs and eight non-RCTs were included. In total, 821 patients with SqCLC were included.ResultsThe response rate (RR) was 2.12 (95% CI: 1.57–2.85, p < 0.00001). The disease control rate (DCR) was 2.38 (95% CI: 1.70–3.32, p < 0.00001). The difference between the two groups was statistically significant. Regarding safety, the incidence rates of the adverse reactions cardiotoxicity, leukopenia, thrombocytopenia, and gastrointestinal reactions were not significantly different between the two groups (OR = 1.70, 95% CI: 0.79–3.68; OR = 0.93, 95% CI: 0.61–1.42; OR = 1.08, 95% CI: 0.71–1.64; OR = 0.86, 95% CI: 0.56–1.30, respectively).ConclusionThe combined treatment had a better therapeutic effect than chemotherapy alone. It did not increase the incidence of adverse reactions in the course of treatment.

Clinical effects of cisplatin plus recombinant human endostatin (rh-endostatin) intratumoral injection on malignant central airway obstruction: a retrospective analysis of 319 cases.

BackgroundPrimary lung cancer with severe central airway obstruction (CAO) is often life-threatening. In this study, we investigated the clinical efficacy and safety of cisplatin plus recombinant human endostatin (rh-endostatin) intratumoral injection in treatment of malignant central airway obstruction (MCAO) caused by primary squamous cell lung cancer.MethodsWe retrospectively analyzed patients with MCAO caused by primary squamous cell lung cancer treated with and without bronchoscopic intratumoral injection of cisplatin plus rh-endostatin between January 2007 and June 2016.ResultsA total of 206 patients received cisplatin plus rh-endostatin intratumoral injection, and 113 without injection. Dyspnea grade, degree of stenosis, quality of life and lung function of all patients were significantly improved at 1 week after treatment compared with baseline. Both groups achieved good airway patency (97.1% vs. 93.8%, P=0.156). Followed up at 2 months, all parameters were improved in the injection group compared with baseline, while no statistical differences were observed in the non-injection group (P>0.05). The injection group achieved airway patency in 155 (75.2%) of 206 patients, which was significantly superior to the non-injection group [20 (17.7%) of 113, P<0.001]. In addition, the restenosis rate of the injection group was lower compared with the non-injection group (22.5% vs. 81.1%, P<0.001, respectively). No serious complications were observed in two groups.ConclusionsCisplatin plus rh-endostatin intratumoral injection is effective and safe for the therapy of MCAO caused by primary squamous cell lung cancer.

Effect of Recombinant Human Endostatin Injection Combined with Chemotherapy on Non-Small Cell Lung Cancer and Activated Circulating Endothelial Cells

To explore the clinical efficacy of recombinant human endostatin injection combined with chemotherapy in the treatment of non-small cell lung cancer and the influence on activated circulating endothelial cells in peripheral blood. A total of 100 non-small cell lung cancer patients were selected and divided into combination and chemotherapy group. Another 30 healthy volunteers were selected as healthy control group. The shortterm treatment effects, drug side effects during treatment and long-term quality of life were compared. Enzyme-linked immunosorbent assay was used to detect the levels of vascular endothelial growth factor and basic fibroblast growth factor. Flow cytometry was used to detect the expression of CD105 and CD146. The total effective rate, leukopenia, thrombocytopenia, nausea/vomiting, peripheral neurotoxicity, cardiac injury and fever were significantly different between the two groups (p<0.05). The physical role, emotional, social and general health scores were significantly higher, and the fatigue, nausea and vomiting, pain, shortness of breath, loss of appetite, constipation, lung cancer specific modules and total symptom subscale score were significantly lower in combination group than those in chemotherapy group (p<0.05). The levels of vascular endothelial growth factor and basic fibroblast growth factor in combination group were decreased and activated circulating endothelial cells were increased after treatment, while in the chemotherapy group, activated circulating endothelial cells only increased in the 4th cycle (p<0.05). Endo combined with chemotherapy has a significant short-term effect in the treatment of non-small cell lung cancer, which can reduce side effects and improve the quality of life.

Endostar Rebuilding Vascular Homeostasis and Enhancing Chemotherapy Efficacy in Cervical Cancer Treatment.

BackgroundThe incidence rate of cervical cancer is the highest in the reproductive tract and is not sensitive to chemotherapy. An appropriate amount of anti-angiogenic agents can reconstruct tumor blood vessels in a short period of time and form vascular homeostasis, increase the function of blood vessel perfusion and reverse the multidrug resistance of chemotherapy, which is also called “vascular normalization.” Endostar (a recombinant human endostatin) was developed by China and as a multi-target anti-angiogenesis agent. Many reports about endostar involved the treatment of non-small cell lung cancer, fewer reports are on cervical cancer.PurposeTo determine whether endostar can rebuild tumor vascular homeostasis and enhance chemotherapy effects for patients with cervical cancer.MethodsIn this study, the patients with cervical cancer within stage IIB2 were selected, endostar combined with cisplatin+paclitaxel neoadjuvant chemotherapy (NACT) before radical surgical operation was adopted, patients outcome and adverse reaction were followed up. The changes of tumor vascular structure and perfusion function before and after endostar given were evaluated by histopathology and dynamic contrast-enhanced magnetic resonance imaging (DEC-MRI). VEGF-Notch signal pathway was detected for the regulating mechanism of vascular proliferation in different groups. GraphPad Prism 6 software was used for statistical analysis of the study results.ResultsEndostar enhanced the short-term (2 year) overall survival (OS), progression-free survival (PFS) rates for cervical cancer patients. All the same, endostar increased long-term (5 year) OS for cervical cancer patients. Endostar therapy exhibited with mild adverse reaction. MRI showed endostar+NACT further reduce tumor volume than NACT alone. The parameters of Ktrans, Ve for DEC-MRI in endostar group exhibited obviously increase than NACT group. Tumor vascular maturation index α-SMA/CD31 in endostar group increased obviously than NACT group, correspondingly Ki67 staining for tumor proliferative rates, lymphovascular space invasion in endostar group further declined than NACT group. The genes and proteins expression of VEGFR2, Notch1, Notch4, Dll4, Jag1 were obviously downregulated in endostar group comparing to NACT group.ConclusionEndostar restored vascular homeostasis in cervical cancer temporarily, enhanced chemotherapeutic agents effects in cervical cancer, increased patient OS ratio. Endostar+NACT treatment may provide a new target therapy for cervical cancer.

Efficacy and safety of recombinant human endostatin combined with radiotherapy or chemoradiotherapy in patients with locally advanced non-small cell lung cancer: a pooled analysis

PurposeTo assess the efficacy and safety of recombinant human endostatin in combination with radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC).MethodsWe searched eligible literature in available databases using combinations of the following search terms: lung cancer, endostatin or endostar, radiotherapy or radiation therapy or chemoradiotherapy. The inclusion criteria were: prospective or retrospective (including single-arm) studies that evaluated the efficacy and safety of endostatin plus radiotherapy (ERT) or concurrent chemoradiotherapy (ECRT) in patients with LA-NSCLC. Primary outcomes included the following: objective response rate (ORR), local control rates (LCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Tests of heterogeneity, sensitivity, and publication bias were performed.ResultsA total of 271 patients with LA-NSCLC from 7 studies were enrolled, including six prospective trials and one retrospective study. The pooled median PFS was 11.3 months overall, 11.2 months in the ECRT group, and 11.8 months in the ERT group. Pooled median OS and ORR were 18.9 months and 77.2% overall, 18.4 months and 77.5% in the ECRT group, and 19.6 months and 76.1% in the ERT group, respectively. The incidences of major grade ≥ 3 AEs for all patients, subgroups of ECRT and ERT were 10.9% vs 11.9% vs 9.4% for radiation pneumonitis, 11.6% vs 12.2% vs 9.4% for radiation esophagitis, 35.5% vs 43.4% vs 0 for leukopenia, 27.8% vs 40.7% vs 2.1% for neutropenia, and 10.5% vs 12.3% vs 2.1% for anemia.ConclusionsCombined endostatin with RT or CCRT is effective and well tolerated in treating LA-NSCLC, and less toxicities occur. Further validation through prospective randomized control trials is required.

A phase II study of rh-endostatin in combination with chemotherapy in human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer (ABC).

1071 Background: There is an urgent need to improve the efficacy of chemotherapy for HER-2 negative patients (pts) who lack anti-HER-2 therapies. Rh-Endostatin (endostar), a recombinant human endostatin, is a potent inhibitor of angiogenesis. This single-arm multicenter phase 2 study was designed to assess the efficacy and safety of endostar combined with chemotherapy in HER-2 negative ABC. Methods: Eligible pts had HER-2 negative inoperable locoregionally recurrent or metastatic breast cancer and an ECOG PS of 0 or 1. Pts with either measurable or nonmeasurable disease were eligible. Endostar (15 mg/m2, continuous infusion, day 1-7) plus chemotherapy were administered every 21 days until disease progression, intolerable toxicity or other reasons. Chemotherapy regimens were selected by investigators based on clinical decision. Primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: From August 2016 to December 2019, 40 female pts were enrolled in 3 centers. The median age was 52. Ten pts were previously untreated and 30 pts had at least 1 line of chemotherapy for advanced disease. 31 pts were triple negative BC (TNBC) and 9 pts were hormonal receptor positive (HR+). Platinum combined with paclitaxel or gemcitabine were administered with endostar in 55% of pts. Others received paclitaxel or gemcitabine combined with endostar. 12 pts achieved a best response of partial response (PR) and 13 pts had stable disease (SD). Among 30 pts with measurable disease, ORR was 40% and DCR was 83%. The ORR for patients treated as the first-line therapy was 75% while as the second line or beyond was 27%. For TNBC and HR+ BC pts, the ORR was 46% and 17% respectively. Median PFS was not reached after a median follow-up of 7.6 months. The most common Grade 3/4 AEs observed during this study were neutropenia (10%), leukopenia (10%) and thrombocytopenia (5%). Conclusions: Endostar combined with chemotherapy was effective and well tolerated for the treatment of HER-2 negative ABC, especially TNBC. Its efficacy and safety could be further studied in randomized trials. Clinical trial information: NCT03907098 .

A Randomized Parallel Controlled Phase II Trial of Recombinant Human Endostatin Added to Neoadjuvant Chemotherapy for Stage III Breast Cancer

BackgroundTo explore the potential advantage of preoperative anti-angiogenosis therapy, we implemented a study to evaluate the efficacy of recombinant human endostatin (EN) in combination with neoadjuvant chemotherapy in the treatment of stage III breast cancer. Patients and MethodsEighty-seven patients were randomized to neoadjuvant TEC (docetaxel, epirubicin, and cyclophosphamide) or to EN+TEC, followed by surgery. The primary endpoint was the objective response rate (ORR). Secondary endpoints included pathologic complete response (pCR), relapse-free survival (RFS), overall survival (OS), and safety. ResultsPatients receiving EN+TEC achieved significantly higher ORR (81.82%; 36/44) compared with those receiving TEC (58.14%; 25/43; P=0.016). There was a non-significant trend of increased pCR with EN treatment (15.91% vs. 6.98%). The median follow-up was 54 months and revealed a significantly higher RFS with EN+TEC (median, 67.3 months; 95% confidence interval [CI], 61.0-73.7 months), compared with TEC (median, 55.0 months; 95% CI, 48.3-61.7 months; P =0.014). EN+TEC also significantly improved OS (74.2 months; 95% CI, 68.9-79.6 months), compared with TEC (59.1 months; 95% CI, 52.0-66.1 months; P =0 .006). The 3- and 5-year OS rates are estimated to be 88.5% and 82.8% with EN+TEC and 76.7% and 54.4% with TEC, respectively. Cox proportional regression analyses showed that EN+TEC was associated with improved OS (hazard ratio, 0.377; 95% CI, 0.418-0.959; P =0 .041). There was no significant difference in adverse events between EN+TEC and TEC. ConclusionThe combination of EN+TEC neoadjuvant chemotherapy significantly improved the ORR and OS, suggesting a benefit of adding anti-angiogenesis to standard chemotherapy in the treatment of locally advanced breast cancer.

Endostar improved efficacy of concurrent chemoradiotherapy with vinorelbine plus carboplatin in locally advanced lung squamous cell carcinoma patients with high serum Lp(a) concentration.

The role of vascular targeting therapy combined with concurrent chemoradiotherapy (CRT) has produced many inconsistent results in locally advanced non-small-cell lung cancer (NSCLC), especially in lung squamous cell carcinoma (LSCC). Lipoprotein (a) [Lp(a)] may be critical in the development of tumor angiogenesis, and its levels are individualized and determined genetically. This study aimed to determine whether Lp(a) is correlated with effects of recombinant human endostatin (Endostar) combined with concurrent CRT for locally advanced LSCC. Patients with locally advanced LSCC from December 2008 to December 2017 were retrospectively analyzed. Patients were divided into two groups: (I) a chemoradiotherapy group (CRT group) which received weekly vinorelbine and carboplatin concurrently with radiotherapy 60Gy, and (II) an Endostar in combination with chemoradiotherapy group (ECRT group) which received Endostar intravenous drip for 1-14 days (every 3 weeks) concurrently with CRT. Fasting venous blood samples for serum Lp(a) in all patients were collected before the treatment. The effect of Endostar was assessed by stratified analysis. A total of 94 patients were recruited in this study. There were 59 cases in the CRT group and 35 cases in the ECRT group. Overall, the median progression-free survival (PFS) was 9.6 vs. 14.2 months (P=0.0671), and the overall survival (OS) was 15.0 vs. 20.6 months (P=0.114), in the CRT and ECRT groups respectively. The median of Lp(a) was 218 mg/L. In patients with serum Lp(a) less than 218 mg/L, the median PFS was 10.0 vs. 9.4 months (P=0.406), and the OS was 15.4 vs. 16.3 months (P=0.958) in the CRT and ECRT groups, respectively. However, in patients with serum Lp(a) higher than 218mg/L, the median PFS was 9.0 vs.15.8 months (P=0.011), and the OS was 14.0 vs. 21.1 months (P=0.055), in the CRT and ECRT groups, respectively. Cox proportional hazard model analysis revealed that a high concentration of Lp(a), ≥218 mg/L, is a prognostic factor for PFS [hazard rate (HR), 0.43 (0.23-0.81)] and OS [HR, 0.52 (0.27-0.98)] in locally advanced LSCC (P<0.05). The serum concentration of Lp(a) may serve as a biomarker to identify the patients who would benefit from Endostar treatment with concurrent CRT in stage III LSCC.

Synergic effect of PD-1 blockade and endostar on the PI3K/AKT/mTOR-mediated autophagy and angiogenesis in Lewis lung carcinoma mouse model

BackgroundImmunotherapy has been shown to be effective as a first-line treatment option for non-small cell lung cancer (NSCLC) patients. Unfortunately, it has failed to acquire an anticipant anti-tumour effect for relatively lower clinical benefit rates. It is therefore important to identify novel strategies for improving immunotherapy. Endostar is a novel recombinant human endostatin that exerts its anti-angiogenic effects via vascular endothelial growth factor (VEGF)-related signalling pathways. Anti-programmed death receptor 1 (PD-1) antibody is an immune checkpoint inhibitor that was developed to stimulate the immune system. In this study, the synergy of PD-1 blockade and endostar was assessed in a lung carcinoma mouse model. MethodsLewis lung carcinoma (LLC)-bearing mice were randomly assigned into three groups: controls, anti-PD-1 and anti-PD-1+endostar. The levels of cytokines such as interleukin (IL)-17, transforming growth factor-β1 (TGF-β1) and interferon-γ (IFN-γ) were measured with enzyme-linked immune sorbent assay (ELISA). The expression of VEGF, CD34 and CD31 was assessed with immunohistochemistry (IHC). The proportion of mature dendritic cells (mDC) and myeloid-derived suppressor cells (MDSC) was analysed with flow cytometry. The major proteins in PI3K/AKT/mTOR and autophagy were quantified with Western blot. ResultsAnti-PD-1 combined with endostar dramatically suppressed tumour growth in LLC mouse models. This synergistic effect resulted in decreased pro-inflammatory cytokine IL-17 and immunosuppressive factor TGF-β1 levels, increased IFN-γ secretion, reduced myeloid-derived suppressor cell (MDSC) accumulation, and reversed CD8 + T cell suppression. The expression of VEGF, CD34 and CD31 was significantly down-regulated, while tumour cell apoptosis and PI3K/AKT/mTOR-mediated autophagy was up-regulated. ConclusionThe combination of anti-PD-1 and endostar has a remarkably synergic effect on LLC tumour growth by means of improving the tumour microenvironment and activating autophagy.