Human Endostatin Research Articles

Inhibitory effect of migration-inducing gene-7-shRNA recombinant retrovirus combined with endostatin on growth and metastasis of hepatoma xenograft

Objective: To investigate the inhibitory effect of migration-inducing gene-7(Mig-7)interfered with retrovirus-mediated RNA(shRNA)combined with recombinant human endostatin(ES)on the growth and metastasis of subcutaneous xenograft of human hepatoma cells in nude mice. Methods: Two Mig-7-mRNA oligonucleotide sequences(Mig-7-shRNA-1 and Mig-7-shRNA-2)and one sequence as a negative control(Mig-7-shRNA-N)were designed. The specific Mig-7-shRNA recombinant retrovirus expression vector plasmid was constructed and used for the transfection of human hepatoma MHCC-97H cells with high expression of Mig-7. The subcutaneous xenograft tumor model of human hepatocellular carcinoma(HCC)in nude mice was established, and according to the condition of transfection and administration, the nude mice were divided into pSIREN-M1 group, pSIREN-MN group, ES group, and pSIREN-M1+ES group. The xenograft tumor volume, mass, and metastasis were compared between groups. Immunohistochemistry was used to observe the formation of vasculogenic mimicry(VM)in xenograft tumor and the difference in tumor microvascular density(MVD), and Western blot was used to measure the expression of Mig-7 and vascular endothelial growth factor(VEGF)in each group. A one-way analysis of variance was used for comparison between groups, and the Fisher's exact test was used for comparison of continuous data between groups. Results: Compared with the pSIREN-MN group, the pSIREN-M1 group had significantly lower xenograft tumor volume, mass, and metastasis rate, Mig-7 expression, and formation of VM(P < 0.05), as well as significantly higher VEGF expression and MVD(P < 0.05). Compared with the pSIREN-MN group, the ES group had significantly lower xenograft tumor volume, mass, and metastasis rate, VEGF expression, and MVD(P < 0.05), as well as significantly higher Mig-7 expression and formation of VM(P < 0.05). Compared with the pSIREN-M1 group and the ES group, the pSIREN-M1+ES group had significantly lower xenograft tumor volume, mass, and metastasis rate, Mig-7 expression, formation of VM, VEGF expression, and MVD(P < 0.05). Conclusion: Mig-7-shRNA recombinant retrovirus combined with ES has a better inhibitory effect on the growth and metastasis of HCC xenograft tumor than Mig-7-shRNA recombinant retrovirus or ES alone. The anti-tumor angiogenesis therapy alone, which targets vascular endothelial cells in vivo, has a limited effect, since it may promote the formation of VM.

Expression of Inhibitor of Differentiation-1 and Its Effects on Angiogenesis in Gastric Cancer.

To explore the effects of recombinant human endostatin (endostar, ES) and cisplatin on the growth of gastric cancer-transplanted tumor in nude mice and the expression of microvessel density (MVD). Human gastric cancer SGC-7901 cells were subcutaneously injected into the armpit of nude mice to prepare cancer-bearing nude mice. A total of 32 cancer-bearing nude mice were divided into four groups (each group with 8 mice). The four groups included control group and other three groups in which mice were treated with 5 mg/kg of ES (group E), 5 mg/kg of cisplatin (group Ci), and 5 mg/kg of ES combined with 5 mg/kg of cisplatin (group C), respectively. MVD was determined by immunohistochemistry, and the expressions of mRNA and protein of inhibitor of differentiation-1 (ID1) and vascular endothelial growth factor (VEGF) were detected with reverse transcription polymerase chain reaction (RT-PCR) and western blot, respectively. Apoptosis was observed with transmission electron microscope. Compared with control group, the sizes and weights of tumors were significantly decreased in other three groups (all p < 0.05). MVD was significantly lower in groups E, Ci, and C than in control group, and in groups E and C than in group Ci (all p < 0.05). Compared with control group, the expressions of mRNA and protein of ID1 and VEGF significantly decreased in groups E and C (all p < 0.05). There were no significant differences in the expressions of mRNA and protein of ID1 and VEGF between group Ci and control group. There was apoptosis in groups E and C, but no apoptosis was found in group Ci and control group. ES can inhibit the growth of gastric cancer cells through suppressing angiogenesis and promoting apoptosis of tumor cell. This study provides a new idea for the treatment of gastric cancer.

Gold Nanoparticle-Mediated Targeted Delivery of Recombinant Human Endostatin Normalizes Tumour Vasculature and Improves Cancer Therapy.

Tumour vasculature is generally disordered because of the production of excessive angiogenic factors by tumour cells, which results in tumour progression and reduces the effectiveness of radiotherapy or chemotherapy. Transient anti-angiogenic therapies that regulate tumour vascular morphology and function and improve the efficiency of antitumour therapy are under investigation. Recombinant human endostatin (Endostar/rhES) is a vascular angiogenesis–disrupting agent that has been used to treat non-small cell lung cancer (NSCLC) in the clinical setting. In this study, we used gold nanoparticles (AuNPs) as a drug-delivery system (DDS) for targeted tumour delivery of rhES for short therapy, which resulted in transient tumour vascular normalization, reduced permeability and hypoxia, strengthened blood vessel integrity, and increased blood-flow perfusion. Moreover, combination therapy with 5-FU over this timeframe was substantially more effective than 5-FU monotherapy. In conclusion, our research demonstrates the potential use of AuNPs as a drug-delivery platform for transporting rhES into a tumour to induce transient tumour vascular normalization and enhance the antitumour efficacy of cytotoxic drugs.

Recombinant human endostatin reduces hypertrophic scar formation in rabbit ear model through down-regulation of VEGF and TIMP-1.

Recombinant human endostatin (Endostar) has been widely used to suppress angiogenesis in carcinoma patients. Hypertrophic scar (HS) tissue, much like a carcinoma, is often associated with angiogenesis. However, there have been few studies conducted on the effects of Endostar on HS or its mechanism. This paper investigated the effects Endostar on the HS of rabbit ears and studied the effects of Endostar on VEGF and TIMP-1 expression. Sixteen New Zealand white rabbits were used to establish HS models. Then, rabbit ears containing HS were randomly assigned to either the Endostar group or the control group. The changes of appearance and histology were evaluated using the naked eye, hematoxylin eosin staining, and a scar elevation index. The VEGF and TIMP-1 expressions were detected by immunohistochemical staining, RT-PCR, and western blot. The thickness of the connective tissue in the Endostar group were thinner, the numbers of micro vessels and fibroblasts were fewer, and the collagen fibers were smoother. Moreover, the mRNA and protein expressions of VEGF and TIMP-1 in the Endostar group were significantly lower than those in the control group. The results suggested that Endostar reduced the formation of HS by down-regulation of VEGF and TIMP-1 expressions.

Cloning and Expression of Recombinant Human Endostatin in Periplasm of Escherichia coli Expression System.

Recombinant human endostatin (rhEs) is an angiogenesis inhibitor which is used as a specific drug in the treatment of non-small-cell lung cancer. In the current research, we developed an efficient method for expressing soluble form of the rhEs protein in the periplasmic space of Escherichia coli via fusing with pelB signal peptide. The human endostatin (hEs) gene was amplified using synthetic (hEs) gene as a template; then, cloned and expressed under T7 lac promoter. IPTG was used as an inducer for rhEs expression. Next, the osmotic shock was used to extraction of protein from the periplasmic space. The presence of rhEs in the periplasmic space was approved by SDS-PAGE and Western blotting. The results show the applicability of pelB fusion protein system usage for secreting rhEs in the periplasm of E. coli in the laboratory scale. The rhEs represents approximately 35 % (0.83mg/l) of the total cell protein. The present study apparently is the first report of codon-optimized rhEs expression as a fusion with pelB signal peptide. The results presented the successful secretion of soluble rhEs to the periplasmic space.

LG-31SUCCESSFUL TREATMENT OF BRAINSTEM PILOMYXOID ASTROCYTOMA USING RECOMBINANT HUMAN ENDOSTATIN COMBINED WITH VINCRISTINE AND CARBOPLATIN: A CASE REPORT

LG-31. SUCCESSFUL TREATMENT OF BRAINSTEM PILOMYXOID ASTROCYTOMA USING RECOMBINANT HUMAN ENDOSTATIN COMBINED WITH VINCRISTINE AND CARBOPLATIN: A CASE REPORT Zhang Jun-Ping, Ge Jing-Jing, Li Cheng, Xue Feng-Jun, and Gao Zhi-Meng; Department of Neuro-Oncology, Sanbo Brain Hospital Capital Medical University, Beijing, China Brainstem glioma of children, especially recurrent pilomyxoid astrocytoma with CNS spread is neuro-oncology challenge. Recombinant human endostatin (rh-ES), an inhibitor of angiogenesis and tumor growth, has been used for treatment of lung cancer, but no experience for pilocytic astrocytoma. Here we report a case of recurrent pilomyxoid astrocytoma that was successfully treated using rh-ES in combination with vincristine (VCR) and carboplatin (CBP). A 12-year-old girl experienced difficulty in walking, dysphagia, bucking and coughing episodes and was diagnosed with a recurrent pilomyxoid astrocytoma in the medulla oblongata, with spreading of supprasellar region, left cerebellar hemisphere and the myelon. She firstly was received chemotherapy with VCR and CBP once a week. Three weeks later, her tumor was progressed and her clinical status deteriorated. Then she was started on rh-ES once per day, on a schedule of two weeks on, two weeks off, in combination with VCR and CBP. Two months after starting with rh-ES treatment, the enhancing mass was decreased. Four months later, the girl experienced improvement in clinical symptomsandsignificant decreaseof tumor. This case suggests that rh-ES may strengthen the effect of VCR and CBP on recurrent pilomyxoid astrocytoma with CNS spread. Neuro-Oncology 18:iii78–iii96, 2016. doi:10.1093/neuonc/now075.31 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Recombinant Human Endostatin Suppresses Mouse Osteoclast Formation by Inhibiting the NF-κB and MAPKs Signaling Pathways.

Rheumatoid arthritis is an autoimmune disease characterized by synovial hyperplasia and progressive joint destruction. As reported previously, recombinant human endostatin (rhEndostatin) is associated with inhibition of joint bone destruction present in rat adjuvant-induced arthritis; however, the effect of rhEndostatin on bone destruction is not known. This study was designed to assess the inhibitory effect and mechanisms of rhEndostatin on formation and function of osteoclasts in vitro, and to gain insight into the mechanism underlying the inhibitory effect of bone destruction. Bone marrow-derived macrophages isolated from BALB/c mice were stimulated with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor to establish osteoclast formation. Osteoclast formation was determined by TRAP staining. Cell viability of BMMs affected by rhEndostatin was determined using a MTT assay. Bone resorption was examined with a bone resorption pits assay. The expression of osteoclast-specific markers was analyzed using quantitative real-time PCR. The related signaling pathways were examined using a Luciferase reporter assay and western blot analysis. Indeed, rhEndostatin showed a significant reduction in the number of osteoclast-like cells and early-stage bone resorption. Moreover, molecular analysis demonstrated that rhEndostatin attenuated RANKL-induced NF-κB signaling by inhibiting the phosphorylation of IκBα and NF-κB p65 nuclear translocation. Furthermore, rhEndostatin significantly inhibited the activation of RANKL-dependent mitogen-activated protein kinases, such as ERK1/2, JNK, and p38. Hence, we demonstrated for the first time that preventing the formation and function of osteoclasts is an important anti-bone destruction mechanism of rhEndostatin, which might be useful in the prevention and treatment of bone destruction in RA.

Efficacy of recombinant human endostatin on relapsed refractory multiple myeloma

Objective To observe the clinical safety and efficacy of recombinant human endostatin (rhES) in patients with relapsed refractory multiple myeloma (RRMM). Methods The clinical data of 25 cases who accepted rhES combined with VD regimen, 22 cases who accepted Tha plus VD regimen, 32 cases who accepted rhES combined with routine regimen and 32 cases who received Tha plus routine regimen were analyzed retrospectively. The overall response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events of the four groups were observed. Results ORRs between rhES combined with VD group (76 %, 19/25) and Tha combined with VD group (59 %, 13/22) and between rhES combined with routine regimen group (44 %, 14/32) and Tha combined with routine regimen group (34 %, 11/32) were no statistical differences (χ2= 1.540, P= 0.215; χ2= 0.591, P = 0.442). The median follow-up time was 7.5 months (0.4 -27.6 months) with 21 cases died, 3 case lost to follow-up. The median PFS and median OS in rhES combined with VD group were 6.9 months (0.5-17.3 months) and 15.7 months (0.5-27.6 months), and those in Tha combined with VD group were 5.2 months (0.5-14.6 months) and 13.4 months (0.5-24.9 months). The difference of PFS between both groups had statistical significance (P= 0.031), but the difference of OS had no (P= 0.129). The median PFS and median OS in rhES combined with routine regimen group were 5.1 months (0.6-11.7 months) and 6.3 months (0.6-18.6 months), and those in Tha combined with routine regimen were 2.7 months (0.4-8.0 months) and 3.4 months (0.4-15.7 months). The differences of PFS between both groups had statistical significance (P= 0.017), but the difference of OS had no (P= 0.123). The adverse effects of all patients mainly included infection caused by bone marrow depression and constipation, but there were no significant differences between the groups (P > 0.05). Conclusions rhES may be an effective supplement to the chemotherapy of RRMM, which will prolong the PFS and improve the life quality. Key words: Multiple myeloma; Endostatin; Relapsed; Refractory

A trail of neoadjuvant recombinant human endostatin in combination with docetaxel, epirubicin, and cyclophosphamide in breast cancer patients.

e12033Background: Endostar (EN), recombinant human endostatin, is available to increase apoptosis of tumor cells due to its antiangiogenesis. It also has synergy with chemotherapy medicine. EN or c...

Effect of Culture Condition Variables on Human Endostatin Gene Expression in Escherichia coli Using Response Surface Methodology.

BackgroundRecombinant human endostatin (rhES) is an angiogenesis inhibitor used as a specific drug for the treatment of non-small-cell lung cancer. As mRNA concentration affects the recombinant protein expression level, any factor affecting mRNA concentration can alter the protein expression level. Response surface methodology (RSM) based on the Box-Behnken design (BBD) is a statistical tool for experimental design and for optimizing biotechnological processes.ObjectivesThis investigation aimed to predict and develop the optimal culture conditions for mRNA expression of the synthetic human endostatin (hES) gene in Escherichia coli BL21 (DE3).Materials and MethodsThe hES gene was amplified, cloned, and expressed in the E. coli expression system. Three factors, including isopropyl β-D-1-thiogalactopyranoside (IPTG) concentration, post-induction time, and cell density before induction, were selected as important factors. The mRNA expression level was determined using real-time PCR. The expression levels of hES mRNA under the different growth conditions were analyzed. SDS-PAGE and western blot analyses were carried out for further confirmation of interest-gene expression.ResultsA maximum rhES mRNA level of 376.16% was obtained under the following conditions: 0.6 mM IPTG, 7 hours post-induction time, and 0.9 cell density before induction. The level of rhES mRNA was significantly correlated with post-induction time, IPTG concentration, and cell density before induction (P < 0.05). The expression of the hES gene was confirmed by western blot.ConclusionsThe obtained results indicate that RSM is an effective method for the optimization of culture conditions for hES gene expression in E. coli.

Advances in research of rh-endostatin in the treatment of cancer

Recombinant human endostatin (Endostar) is a broad spectrum molecular targeted drug on anti-angiogenesis that the main evidence-based data is combined chemotherapy treatment of advanced non-small cell lung cancer (NSCLC). In recent years, the researches of recombinant human endostatin used in the treatment of various malignant tumors are on the increase and achieve good effect. In addition, the researches about combined treatment methods, routes of administration, methods of medication are carried out gradually, which will be conducive to the reasonable application in clinical. Key words: Neoplasms; Drug therapy; Recombinant human endostatin

33. Advancing a State of the Art Gene Therapy Called OXB-202 That Resists Corneal Rejection in High Risk Patients

Due to both the avascularity of the cornea and the relatively immune-privileged status of the eye corneal transplantation is one of the most successful clinical transplant procedures. However in high risk patients, which account for >20% of the 100,000 transplants carried out worldwide each year, the rejection rate is high due to vascularization of the recipient corneal bed. In some of these patients the prognosis is extremely poor, with grafts failing at an accelerating rate to the point where patients are no longer considered suitable for further transplants and are left blind, despite an otherwise normally functioning visual system. The main reason for graft failure is irreversible immunological rejection and it is therefore unsurprising that neovascularization (both pre-and post-grafting) is a significant risk factor for subsequent graft failure. Neovascularization is thus an attractive target to prevent corneal graft rejection. OXB-202 (previously known as EncorStat®) is a human donor cornea modified prior to transplant by ex vivo genetic modification with genes encoding secretable forms of the angiostatic human proteins, endostatin and angiostatin. This is achieved using a lentiviral vector derived from the Equine Infectious Anaemia Virus (EIAV) called pONYK1EiA, which subsequently prevents rejection by suppressing neovascularization. Previously we have shown that rabbit corneas treated with pONYK1EiA substantially suppress corneal neovascularization, opacity and subsequent rejection in rabbit models of cornea graft rejection (Parker et al, 2014). We will present data from a 3-month GLP toxicology and biodistribution safety study of pONYK1EiA modified rabbit corneas in a rabbit corneal transplant model. In particular, the GLP study has been designed to include a number of high content in-life assessments that include regular slitlamp ophthalmic examinations, evaluation of corneal thickness and endothelial cell density using pachymetry and specular microscopy respectively and intraocular pressure measurements. We will present a summary of these data to show that there are no safety issues with pONYK1EiA modified corneas. The GLP safety study data to be presented supports the evaluation of OXB-202 corneas in a First-in-Man trial. The toxicology study, GMP manufactures and clinical development of OXB-202 has been supported by the UK Technology Strategy Board (Innovate UK).

Infra Red Dye and Endostar Loaded Poly Lactic Acid Nano Particles as a Novel Theranostic Nanomedicine for Breast Cancer.

Endostar, a novel recombinant human endostatin, has been proven to inhibit tumor angiogenesis and is utilized as an anticancer drug. While free drugs can display limited efficacy, nanoscaled anticancer drugs have been fabricated and proven to possess superior therapeutic effects. Poly(lactic acid) (PLA) is a FDA-approved biomaterial displaying excellent biocompatibility and low toxicity. In this study, Endostar-loaded PLA nanoparticles (EPNPs) were first prepared, and a near-infrared (NIR) dye, IRDye 800CW, was conjugated to the surface for detecting nanoparticle biodistribution through fluorescence molecular imaging (FMI) using an orthotopic breast tumor mouse model. The antitumor efficacy of EPNPs was examined using bioluminescence imaging (BLI) and immunohistology. To further improve the antitumor effects, we combined EPNPs with zoledronic acid monohydrate (ZA), which is known to decrease the tumor-associated macrophages (TAM) and inhibit tumor progression. We found that EPNPs decreased human umbilical vein endothelial cell (HUVEC) viability by inhibiting tumor growth gene expression more significantly than free Endostar in vitro. In vivo, EPNPs displayed better tumor growth inhibitory effects compared with free Endostar, and the combination of EPNPs with ZA exhibited more significant antitumor effects. As confirmed by CD31 and CD11b immunohistochemistry, the combination of EPNPs and ZA showed synergistic effects in reducing tumor angiogenesis and TAM accumulation in tumor regions. Taken together, this study presents a novel and effective form of nanoscaled Endostar for the treatment of breast cancer that displays synergistic antitumor effects in combination with ZA.

Production of a therapeutic protein by fusing it with two fragments of the carboxyl-terminal peptide of human chorionic gonadotropin β-subunit in Pichia pastoris.

To produce a therapeutic protein (endostatin) by fusion with two fragments of the carboxyl-terminal peptide (CTP) of the human chorionic gonadotropin β-subunit in Pichia pastoris. Two CTP sequences were fused to the C-terminal of human endostatin, and the fusion protein (endo-CTP) was expressed by P. pastoris. Endo-CTP inhibited proliferation of endothelial cells with an IC50 of 7μgml(-1), and 30% of cells were annexin V-positive after treatment with 20μg endo-CTP ml(-1) for 48h. Migration of endothelial cells was inhibited by endo-CTP in a concentration-dependent manner. The half-life of endo-CTP in Sprague-Dawley rats was much longer than that of its commercial counterpart (Endostar). A long-acting endostatin can be produced using CTP technology.

Clinical observation of body-gamma knife combined with recombinant human endostatin injection (Endostar) as the therapy in the elderly patients with advanced non-small cell lung cancers

Objective To explore the efficacy and safety of human recombinant vascular endothelial inhibition (en) combined with gamma knife in the treatment of elderly advanced non-small cell lung cancer patents. Methods Totally 38 cases of senile non-small cell lung cancer patients were divided into two groups: A group was treatment group with 17 cases of recombinant human endostatin combined with gamma knife, group B was control group with 21 cases of patients receiving body gamma knife alone. Recombinant human endostatin was given intravenously 15 mg per day in 500 ml of saline for 3~4 hours for 14 days a cycle, and the total dose of body gamma knife therapy was 36~48 Gy/10~12f. Results The response rate (RR) of groups A and B were 58.82% and 57.14% without statistical difference. One-year survival rate of groups A and B were 47.06% and 38.09%, respectively; and there was no statistical significance. The main side-effects of both groups were bone marrow suppression and gastrointestinal reactions, but no statistical difference was observed. Two groups of patients' quality of life were improved without statistical difference (P>0.05). Conclusions Body-gamma knife therapy combined with recombinant human endostatin in elderly advanced non-small cell lung cancer patients has better efficacy such as CR rate and long-term survival, and similar side-effects. Key words: Radiosurgery; Endostatins/TU; Carcinoma, non-small-cell lung/TH

Effect of recombinant human endostatin onradiotherapy for esophagus cancer.

To investigate the effect of radiotherapy plus recombinant human endostatin (RH-endostatin) on esophageal cancer and its mechanism. A total of 50 nudemice were equally randomized into control group, radiotherapy group, and combined therapy group I, II, and III after inoculating with Eca109 cell suspension (1×10(7)cells/mL). On the day of grouping, control group and radiotherapy group were injected normal saline, while radiotherapy group and 3 combined therapy groups received radiotherapy; besides, combined therapy group I, II, and III was injected RH-endostatin of 2.5, 5, 10mg/kg respectively. After 3-week therapy, the tumors of each group were collected and microvessel density and VEGF expression in tumors were determined. Invitro, Eca109 cells were divided into control group, radiotherapy group, and combined therapy group. Forty-eight hours after treatment, cell cycle distribution and apoptosis rate were detected, and the activity of VEGF signal paths was semiquantitatively analyzed. Since the 6th day of treatment, the relative tumor proliferation rate of combined therapy group II was lower than radiotherapy group (P<0.05) and ≤40% since the 15th day. Average microvessel density and EGFR expression in combined therapy group II were lower than radiotherapy group (P<0.05). Invitro, the cell percentage in S and G2/M phase of combined therapy group cells was lower than that in radiotherapy group cells, while the apoptosis rate and the expression of VEGF, AKT, p-AKT, ERK1/2 and p-ERK1/2 in combined group were higher than that in radiotherapy group (P<0.05). RH-endostatin promotes the efficacy of radiotherapy on esophageal cancer, which may be partly realized by inhibiting the activity of VEGF related signal paths.

Health Resource Utilization in Patients with Advanced Non-Small Cell Lung Cancer Receiving Chemotherapy in China.

Chemotherapy is the preferred treatment regimen for advanced lung cancer patients. This study investigated the health resources utilized by and medical expenses of patients with non-small cell lung cancer (NSCLC) as well as the influence of various chemotherapy regimens on the final medical costs in China. The aim of this study was to provide physicians with a reference to use as the basis for their choice of treatment. Data were collected from the Shanghai Chest Hospital's medical charts and billing database. The collected patient information included the baseline characteristics, medical history, chemotherapy regimens, and medical costs, which were used to estimate the health resources utilized by patients and the cost of treatment. This study included 328 patients, and the average total medical cost was $US14,165. This cost included drugs, which accounted for as much as 78.91% of the total cost, and chemotherapy drugs, which accounted for 51.58% of total drug expenses. The most frequently utilized chemotherapy drug was carboplatin, and the most expensive chemotherapy drug was erlotinib. In drug combinations, gemcitabine was utilized most frequently, the combination of gemcitabine and paclitaxel was the most expensive, and cisplatin was the least expensive drug. Epidermal growth factor receptor-positive patients were treated with targeted drug therapy (icotinib, erlotinib, and gefitinib). The use of recombinant human endostatin was often combined with a vinorelbine plus cisplatin regimen. Traditional Chinese medicines were the most frequently utilized non-chemotherapy drugs, and these drugs were also the most expensive. The final cost significantly depended on the specific chemotherapy regimen; thus, the rationale and cost of the chemotherapy regimen and adjuvant chemotherapy should be considered in patients with advanced NSCLC.

Endostatin combined with radiotherapy suppresses vasculogenic mimicry formation through inhibition of epithelial-mesenchymal transition in esophageal cancer.

The growth of solid tumors requires angiogenesis to provide oxygen and nutrients and to support cell proliferation. The switch from an avascular to a vascular phenotype is typically related to acceleration of tumor growth. Anti-angiogenic therapy is becoming a very promising way for malignant tumors. Meanwhile, malignant tumor cells themselves were able to develop the formation of cell-lined vessels that contribute to tumor neovascularization and supply the nutrients and oxygen, which is called vasculogenic mimicry (VM). However, the molecular mechanism of VM remains unclear. The purpose of this study was to investigate the efficacy of the novel recombinant human endostatin (rh-Endo) protein combined with radiotherapy on human esophageal squamous cell carcinoma (ESCC) cell lines Eca-109 and TE13. Our results showed that rh-Endo combined with radiotherapy significantly inhibited the proliferation, migration, invasion, and VM of human esophageal cancer cells in a dose-dependent manner; however, it has no direct effect on apoptosis of carcinoma cells, which indicated that rh-Endo combined with radiotherapy significantly changed the microenvironment of esophageal carcinoma, and played an important role in preventing distant metastasis. Our findings suggested that rh-Endo inhibited the metastasis of esophageal cancer and the activation of AKT pathway, and the down-regulation of epithelial-mesenchymal transition (EMT) may be associated with such effect of rh-Endo. These results also supported the bright prospect of rh-Endo combined with radiotherapy for clinical applications in the future.

Human Recombinant Endostatin Combined with Cisplatin Based Doublets in Treating Patients with Advanced NSCLC and Evaluation by CT Perfusion Imaging.

To study the effectiveness of human recombinant endostatin injection (Endostar®) combined with cisplatin doublets in treating advanced non-small cell lung cancer (NSCLC), and to evaluate outcome by CT perfusion imaging. From April 2011 to September 2014, 76 patients with advanced NSCLC who were treated with platinum-based doublets were divided into group A (36 patients) and group B (40 patients). Endostar® 15 mg/day was administered 4 days before chemotherapy and combined with chemotherapy from day 5 in group A, and combined with chemotherapy from the first day in Group B. Endostar® in the two groups was injected intravenously for 14 days. Treatment effectiveness in the two groups differed with statistical significance (p<0.05). Effectiveness evaluated by CT perfusion imaging, BF, BV, MTT and PS also demonstrated significant differences (all p<0.05). Adverse reactions in the two groups did not significantly vary (p>0.05). The response rate with Endostar® administered 4 days before chemotherapy and combined with chemotherapy from day 5 in group A was better than Endostar® combined with chemotherapy from the first day, and CT perfusion imaging could be a reasonable method for evaluation of patient outcomes.

Recombinant human endostatin enhances the radioresponse in esophageal squamous cell carcinoma by normalizing tumor vasculature and reducing hypoxia.

The aim of this study was to investigate the effect of recombinant human endostatin (rh-Endo) in combination with radiation therapy (RT) on esophageal squamous cell carcinoma (ESCC) and explore the potential mechanisms. ECA109-bearing nude mice were administered RT and/or rh-Endo treatment. Tumor volume, survival, hypoxia and vascular parameters were recorded during the treatment schedule and follow-up as measures of treatment response. ESCC cell lines (ECA109 and TE13) and human umbilical vein endothelial cells (HUVECs) were developed to investigate the outcomes and toxicities of rh-Endo and RT in vitro. Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were also evaluated. In vivo studies of ECA109-bearing xenografts showed that rh-Endo improved the radioresponse, with normalization of tumor vasculature and a reduction in hypoxia. In vitro studies showed that rh-Endo did not radiosensitize ESCC cell lines but did affect endothelial cells with a time- and dose-dependent manner. Studies of the molecular mechanism indicated that the improved radioresponse might be due to crosstalk between cancer cells and endothelial cells involving HIF and VEGF expression. Our data suggest that rh-Endo may be a potential anti-angiogenic agent in ESCC especially when combined with RT. The improved radioresponse arises from normalization of tumor vasculature and a reduction in hypoxia.