Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Standard treatments for canine hemangiosarcoma include surgery and chemotherapy with doxorubicin, but in spite of treatment most dogs with this disease die within 6 months of diagnosis. Tumor growth and metastasis are angiogenesis dependent. Antiangiogenic drugs such as minocycline may provide therapeutic benefits in cancer patients. The purpose of this prospective study was to evaluate the efficacy of chemotherapy with doxorubicin and minocycline, an antiangiogenic agent, in dogs with hemangiosarcoma. Eighteen dogs with histologically confirmed hemangiosarcoma of any stage were treated with doxorubicin, cyclophosphamide, and minocycline. Complete staging was performed before and during the treatment period to assess remission status and response to therapy. No statistically significant difference was found in survival between the dogs treated with chemotherapy and minocycline, and historical controls consisting of dogs that received chemotherapy alone. Postmortem examination revealed widespread metastasis, suggesting that minocycline is ineffective as a single antiangiogenic agent in canine hemangiosarcoma.
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PMID:Canine hemangiosarcoma treated with standard chemotherapy and minocycline. 1093 88

A transgenic mouse model was used to evaluate the effect of endostatin treatment on spontaneous tumorigenesis. In this model system, female mice develop multiple mammary adenocarcinomas and male mice develop prostate cancer. Female mice treated with mouse endostatin during a 12-15-week period showed delayed tumor development by 4-6 weeks and significantly decreased tumor burden. Furthermore, endostatin treatment reduced the number of malignant lesions per mouse. In a separate set of experiments, male mice treated with endostatin showed a survival advantage, and their life spans were prolonged by 10.5 weeks over control animals. These data demonstrate that mouse endostatin is effective in delaying spontaneous tumor development and growth.
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PMID:Effect of endostatin on spontaneous tumorigenesis of mammary adenocarcinoma in a transgenic mouse model. 1096 78

Antiangiogenic therapy is a promising new strategy to inhibit tumor growth and formation of metastases. Vascular endothelial growth factor (VEGF) and its receptors, VEGF-receptor 1 (VEGF-R1; FLT-1) and VEGF-R2 (KDR), have been shown to play a major role in tumor angiogenesis. PTK787/ZK 222584, a specific inhibitor of both VEGF-receptor tyrosine kinases, was investigated for its antitumoral and antiangiogenic activity in a murine renal cell carcinoma model. After intrarenal application of the renal carcinoma cells, mice develop a primary tumor and metastases to the lung and to the abdominal lymph nodes. Daily oral therapy with PTK787/ZK 222584 at a dose of 50 mg/kg resulted in a significant decrease of 61 and 67% in primary tumors after 14 and 21 days, respectively. The occurrence of lung metastases was significantly inhibited at both time points (98% reduction and 78% reduction, respectively). After 14 days, no lymph node metastases developed in the PTK787/ZK 222584-treated group, whereas after 21 days of treatment, the lymph node metastases were reduced by 87%. Vessel density in tumor tissues, detected by immunohistochemistry with an anti-CD31 antibody, was significantly decreased by PTK787/ZK 222584. Using color Doppler imaging ultrasound, significant changes in blood flow in the tumor feeding renal artery were found under treatment with PTK787/ZK 222584. Blood flow changes correlated with changes in vessel density but not with tumor volume. The compound was well tolerated in all in vivo experiments and had no significant effects on body weight or general well-being of the animals. This was in contrast to the animals treated with the antiangiogenic agent TNP-470. s.c. therapy with 30 mg/kg TNP-470 every other day had to be discontinued after 13 days because of animal weight loss (>20%) and ataxia. These results demonstrate that PTK787/ZK 222584 is a potent inhibitor of tumor growth, metastases formation, and tumor vascularization in murine renal cell carcinoma. Furthermore, we have been able to demonstrate that color Doppler imaging ultrasound can be used to measure blood flow to a tumor and that flow correlates with vessel density. Thus, this may be a valuable noninvasive method for monitoring the effects of antiangiogenic agents such as PTK787/ZK 222584 on tumor vasculature.
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PMID:Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. 1098 92

Tumor angiogenesis is one of the most important fields of cancer research. It is important to identify the putative targets for antiangiogenic strategies. To date, a number of angiogenic agents have been identified: bFGF, the different VEGF isoforms, integrins, proteases (matrix metalloproteases and serine proteases),... Furthermore, several physiological anti-angiogenic agents have been isolated such as endostatin, angiostatin, 16 K prolactin,.... The recent development of mice deficient for one gene involved during angiogenesis gives a new insight into the molecular mechanisms regulating this process. It leads to the identification of plasminogen activator inhibitor-1 or PAI-1 as a new target for tumor treatment. Although, PAI-1 is very attractive as a target for new therapeutic strategies, a better understanding of its mechanism of action is needed urgently.
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PMID:[Preclinical features of anti-angiogenesis therapy]. 1098 53

Here we report the inhibition of cellular invasion by a recombinant mouse endostatin and the possible mechanism of the inhibition. Endostatin significantly reduced endothelial as well as tumor cellular invasion into the reconstituted basement membrane in vitro. Gelatin zymographic analysis revealed that the activation of promatrix metalloproteinase-2 (proMMP-2) that was secreted from endothelial cells was blocked upon endostatin treatment. Studies with recombinant MMPs confirmed that endostatin inhibited proMMP-2 activation, mediated by both membrane-type 1 MMP and 4-aminophenylmercuric acetate. Furthermore, enzymatic assays using a peptide substrate demonstrated that endostatin inhibited the catalytic activities of both MMP-2 and membrane-type 1 MMP. Finally, coimmunoprecipitation experiments revealed that endostatin formed a stable complex with proMMP-2. These novel findings would, at least in part, explain the mechanism of the potent antiangiogenic and antitumor activities of endostatin.
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PMID:Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase. 1103 81

N-Acetylcysteine (NAC) is a drug bearing multiple preventive properties that can inhibit genotoxicity and carcinogenicity. NAC also inhibits invasion and metastasis of malignant cells, as well as tumor take. We recently demonstrated the effects of NAC on Kaposi's sarcoma cells supernatant-induced invasion in vitro and angiogenesis in vivo. Many anticancer agents act through cytotoxicity of rapidly proliferating cells and several antineoplastic drugs induce apoptosis of cancer cells. Since endothelial cells are the target for the inhibition of angiogenesis, we wanted to verify that NAC, while inhibiting tumor vascularization and endothelial cell invasion would not induce endothelial cell apoptosis. We tested the ability of NAC to modulate apoptosis and cytogenetic damage in vitro and to promote differentiation on a reconstituted basement membrane (matrigel) in two endothelial cell lines (EAhy926 and HUVE). Treatment with NAC protected endothelial cells from TGF-beta-induced apoptosis and paraquat-induced cytogenetic damage. Therefore, NAC acts as an antiangiogenic agent and, at the same time, appears to prevent apoptosis and oxygen-related genotoxicity in endothelial cells.
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PMID:Antiapoptotic and antigenotoxic effects of N-acetylcysteine in human cells of endothelial origin. 1106 41

We describe a technique for the treatment of malignant brain tumors based on local delivery of the anti-angiogenic protein endostatin from genetically engineered cells encapsulated in ultrapure sodium alginate. Alginate consists of L-guluronic and D-mannuronic acid, which in the presence of divalent cations forms an extended gel network, in which cells reside and remain immunoisolated, when implanted into the rat brain. Here, we show that endostatin-transfected cells encapsulated in alginate maintain endostatin secretion for at least four months after intracerebral implantation in rats. During the implantation period 70% of the encapsulated cells remained viable, as opposed to 85% in in vitro-cultured capsules. Rats that received transplants of BT4C glioma cells, together with endostatin-producing capsules (0.2 microg/ml per capsule), survived 84% longer than the controls. The endostatin released from the capsules led to an induction of apoptosis, hypoxia, and large necrotic avascular areas within 77% of the treated tumors, whereas all the controls were negative. The encapsulation technique may be used for many different cell lines engineered to potentially interfere with the complex microenvironment in which tumor and normal cells reside. The present work may thus provide the basis for new therapeutic approaches toward brain tumors.
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PMID:Local endostatin treatment of gliomas administered by microencapsulated producer cells. 1113 44

Research studies suggest that tumor-related angiogenesis contributes to the phenotype of malignant gliomas. We assessed the effect of local delivery of the angiogenesis inhibitor endostatin on human glioma cell line (U-87MG) xenografts. Baby hamster kidney (BHK) cells were stably transfected with a human endostatin (hES) expression vector and were encapsulated in alginate-poly L-lysine (PLL) microcapsules for long-term delivery of hES. The release of biologically active endostatin was confirmed using assays of bovine capillary endothelial (BCE) proliferation and of tube formation. Human endostatin released from the microcapsules brought about a 67. 2% inhibition of BCE proliferation. Furthermore, secreted hES was able to inhibit tube formation in KDR/PAE cells (porcine aortic endothelial cells stably transfected with KDR, a tyrosine kinase) treated with conditioned U-87MG medium. A single local injection of encapsulated endostatin-secreting cells in a nude mouse model resulted in a 72.3% reduction in subcutaneous U87 xenografts' weight 21 days post treatment. This inhibition was achieved by only 150.8 ng/ml human endostatin secreted from 2 x 10(5) encapsulated cells. Encapsulated endostatin-secreting cells are effective for the treatment of human glioblastoma xenografts. Continuous local delivery of endostatin may offer an effective therapeutic approach to the treatment of a variety of tumor types.
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PMID:Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. 1113 44

Endostatin is a novel antiangiogenic agent currently in phase I trials. In the context of this trial, we are evaluating the use of non-invasive imaging with PET to determine the relationship between tumor blood flow and glucose metabolism in imaged tumors from treated patients.Ten patients have been treated with escalating daily iv Endostatin doses of 30 to 180 mg/m(2). PET images were obtained before the start of therapy and again after 28 days of treatment. Each patient was scanned with Oxygen-15 labeled water for estimation of tumor blood flow and Flourine-18 labeled FDG to estimate tumor metabolic activity. In most cases, two distinct tumor-bearing sites were analyzed in each patient. Thus, a total of 19 tumors were imaged. Regional blood flow and standard uptake values (SUV) were computed at baseline and 28 days post treatment and the percentage change in blood flow and SUV plotted as a function of Endostatin dose.Both blood flow and glucose metabolism in the imaged tumors were observed to increase in patients treated with </=60 mg/m(2)/d, but became uncoupled in the tumors imaged from patients treated at the 180 mg/m(2)/d dose level. Thus, in patients receiving Endostatin at a dose of 180 mg/m(2)/d, blood flow decreased but glucose metabolism increased. This relationship is displayed in Figure 1 below.
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PMID:9:00-9:15. Antiangiogenic Treatment with Endostatin Results in Uncoupling of Blood Flow and Glucose Metabolism in Human Tumors. 1115 Jul 54

The purpose of this study was to determine if the first-pass of FDG can be used to measure regional blood flow in tumors in the absence of perfusion imaging with a known blood flow tracer.PET scans were obtained in patients being evaluated for tumor perfusion and metabolism in a Phase I dose escalating protocol for Endostatin, a novel antiangiogenic agent. A two minutes perfusion scan was done with a bolus injection of 60 mCi of O-15 labeled water followed by a 10 mCi dose of FDG and four sequential scans consisting of a first pass two minutes scan and three 15 minutes scans. Regions of interest were drawn on two tumor sites for each scan. Blood flow was computed using a one-compartment model previously published by the authors. Linear regression analysis was carried out between the first pass FDG measured blood flow and O-15 measured blood flow (Figure 1).Blood flow estimated from the first pass of FDG was linearly correlated with O-15 measured blood flow with an intercept of 0.01, slope of 0.86, and r squared regression coefficient of 0.74 (R = 0.86) for blood flow values of up to 0.6 ml/min/gm of tissue. These results suggests that in the absence of a perfusion tracer, the first pass of FDG provides an estimate of perfusion in a tumor within the limitations of incomplete extraction of FDG compared to O-15 water.
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PMID:9:30-9:45. First Pass FDG Measured Blood Flow in Tumors: A Comparison with O-15 Labeled Water Measured Blood Flow. 1115 Jul 56


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