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)

Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. We demonstrate that a mutated form of human endostatin (P125A) can inhibit the angiogenic switch in the C3(1)/Tag mammary cancer model. P125A has a stronger growth-inhibitory effect on endothelial cell proliferation than wild-type endostatin. We characterize the angiogenic switch, which occurs during the transition from preinvasive lesions to invasive carcinoma in this model, and which is accompanied by a significant increase in total protein levels of vascular endothelial growth factor (VEGF) and an invasion of blood vessels. Expression of the VEGF(188) mRNA isoform, however, is suppressed in invasive carcinomas. The VEGF receptors fetal liver kinase-1 (Flk-1) and Fms-like tyrosine kinase-1 (Flt-1) become highly expressed in epithelial tumor and endothelial cells in the mammary carcinomas, suggesting a potential autocrine effect for VEGF on tumor cell growth. Angiopoietin-2 mRNA levels are also increased during tumor progression. CD-31 (platelet-endothelial cell adhesion molecule [PECAM]) staining revealed that blood vessels developed in tumors larger than 1 mm The administration of P125A human endostatin in C3(1)/Tag females resulted in a significant delay in tumor onset, decreased tumor multiplicity and tumor burden and prolonged survival of the animals. Endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls. However, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased in the endostatin-treated group compared with controls. These results demonstrate that P125A endostatin inhibits the angiogenic switch during mammary gland adenocarcinoma tumor progression in the C3(1)/Tag transgenic model.
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PMID:Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin. 1220 72

SU5416 is a small molecule antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF) stimulation of the KDR tyrosine kinase receptor. In this Phase I dose escalation trial, a weekly dose schedule of SU5416 was tested whereby an initial 5-day loading dose was followed by weekly maintenance infusions. The start dose was 20 mg/m(2) for the loading dose followed by 65 mg/m(2) for the weekly infusions. Dose escalations occurred at 33% until a final dose of 65 mg/m(2) (loading dose) and 190 mg/m(2) (weekly infusion) was obtained. Twenty-two patients were treated at five dose levels; tumor types included gastrointestinal (8), breast (3), lung (4), sarcoma (2), and other (5). The most common serious drug-related toxicity was headache, often associated with nausea and vomiting. Grade 1 and 2 toxicities included headache, nausea, vomiting, asthenia, pain at the infusion site, phlebitis, change in voice, and fevers. Of 19 evaluable patients, 4 obtained clinical benefit as defined by tumor regression (1) or disease stabilization for at least 12 weeks (3). Pharmacokinetic data revealed that the weekly infusion schedule prevented the reported 50-60% induction in SU5416 clearance observed with either daily or twice weekly dosing. Higher baseline levels of urine VEGF were observed in the 4 patients who gained clinical benefit, suggesting this may be a useful marker for predicting response to anti-VEGF therapies. Our results suggest that a weekly schedule of SU5416 shows signs of biological activity and is well tolerated at doses up to 145 mg/m(2).
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PMID:Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. 1223 19

Delayed gastric ulcer healing is a well recognized problem associated with the use of cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (flurbiprofen), a nitric oxide-releasing COX inhibitor (HCT-1026), and a selective COX-2 inhibitor (celecoxib) on gastric ulcer healing, angiogenesis, and platelet/serum levels of vascular endothelial growth factor (VEGF) and endostatin. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week. Celecoxib and flurbiprofen impaired angiogenesis and delayed ulcer healing, as well as increasing serum endostatin levels relative to those of VEGF. HCT-1026 did not delay ulcer healing nor impair angiogenesis, and also did not change the ratio of serum endostatin to VEGF. Incubation of human umbilical vein endothelial cells with serum from celecoxib- or flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay ulcer healing, namely, through altering the balance of anti- and proangiogenic factors in the serum. The absence of a delaying effect of HCT-1026 on ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro- and antiangiogenic growth factors.
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PMID:Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance. 1223 50

There is considerable evidence to support an immunopathogenic basis of psoriasis. However, changes such as altered angiogenesis have also been implicated in the pathogenesis of psoriasis. AE-941 (Neovastat; Aeterna Laboratories, Quebec City Quebec, Canada) is a naturally occurring product currently in clinical investigation that blocks two main mechanisms of angiogenesis activation, namely, vascular endothelial growth factor and matrix metalloproteinase. We hypothesized that psoriasis could be modulated by inhibiting the neovascularization of psoriatic plaques. We conducted a randomized dose-comparison trial to evaluate the safety and potential therapeutic benefit of AE-941, administered orally to patients with psoriasis. Forty-nine patients with psoriasis were enrolled and assigned to receive AE-941 at 30, 60, 120, or 240 mL/d for 12 weeks. Patients were followed up for another 12-week period. Improvement in the Psoriasis Area and Severity Index (PASI) score was observed in 50%, 41.7%, and 30.8% of the patients receiving 240, 120, and 60 mL/d, respectively. No patients receiving a dosage 30 mL/d showed a PASI score improvement. A statistically significant improvement with increasing dose was observed for the PASI score, severity of itch, and the physician's global assessment. The most commonly reported nonserious drug-related adverse events affected the gastrointestinal system in 12 of 49 patients (primarily nausea, diarrhea, vomiting, flatulence, and constipation) and the skin and appendages in 4 of 49 patients (primarily acne and rash). This randomized phase I/II study provides evidence that the antiangiogenic agent AE-941 offers a new therapeutic approach to the management of psoriasis.
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PMID:Neovastat (AE-941), an inhibitor of angiogenesis: Randomized phase I/II clinical trial results in patients with plaque psoriasis. 1227 Dec 97

Endostatin and angiostatin are known as tumor-derived angiogenesis inhibitors, but their mechanisms of action are not yet completely defined. We report here that endostatin and angiostatin, delivered by adenoviral vectors, reduced in vitro the neovessel formation in the mouse aortic ring assay by 85 and 40%, respectively. We also demonstrated in vivo that both endostatin and angiostatin inhibited local invasion and tumor vascularization of transplanted murine malignant keratinocytes, and reduced by 50 and 90% the development of highly vascularized murine mammary tumors. This inhibition of tumor growth was associated with a reduction of tumor vascularization. Expression analysis of vascular endothelial growth factor (VEGF) carried out in the mouse aortic ring model revealed a 3- to 10-fold down-regulation of VEGF mRNA expression in endostatin-treated rings. A similar down-regulation of VEGF expression at both mRNA and protein levels was also observed in the two in vivo cancer models after treatment with each angiogenesis inhibitor. This suggests that endostatin and angiostatin effects may be mediated, at least in part, by their ability to down-regulate VEGF expression within the tumor. This work provides evidence that endostatin and angiostatin act on tumor cells themselves.
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PMID:The antitumoral effect of endostatin and angiostatin is associated with a down-regulation of vascular endothelial growth factor expression in tumor cells. 1235 94

The interaction between cancer cells and their microenvironment is a promising area for the development of novel therapeutic anti-cancer modalities. The formation of new blood vessels, angiogenesis, is an important step in cancer progression. Angiogenesis is a complex multistep process involving close orchestration of endothelial cells, extracellular matrix, and soluble factors. Essentially every step has been found to be regulated by inducers and inhibitors. Prostate cancer has the ability to produce angiogenic factors such as metalloproteinases, vascular endothelial growth factor, fibroblast growth factor 2, transforming growth factor-beta and cyclooxygenase-2. In several studies in prostate cancer an increased microvessel density is associated with poorer prognosis. On the other hand several endogenous inhibitors of angiogenesis have been described in prostate cancer e.g., angiostatin, endostatin, prostate specific antigen (PSA), thrombospondin-1, interleukin 10, interferons and retinoids. The expanding insight in the process of angiogenesis has resulted in a large number of pharmaceutical agents that have been tested in preclinical studies and are currently tested in clinical trials. These agents inhibit endothelial cell proliferation or migration and induce apoptosis. This ultimately will affect the formation of new vessels thereby inducing tumor dormancy. Because antiangiogenic treatment is cytostatic rather than cytotoxic, patients will need long-term therapy to prevent regrowth of the tumor. Prostate cancer is an ideal tumor for antiangiogenic studies because of the availability of a reliable tumor marker, PSA, the indolent clinical course of this cancer and the low rate of proliferation even in metastatic sites. Furthermore, clinical studies showed limited side effects, which is advantageous in this elderly patient group. Whether the ultimate antiangiogenic treatment is effective as a single agent or in combination with radiation therapy, chemotherapy or immunotherapy remains to be determined.
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PMID:Angiogenesis in prostate cancer: its role in disease progression and possible therapeutic approaches. 1243 18

To examine whether the lack of sufficient neoangiogenesis in systemic sclerosis (SSc) is caused by a decrease in angiogenic factors and/or an increase in angiostatic factors, the potent proangiogenic molecules vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, and the angiostatic factor endostatin were determined in patients with SSc and in healthy controls. Forty-three patients with established SSc and nine patients with pre-SSc were included in the study. Serum levels of VEGF, basic fibroblast growth factor and endostatin were measured by ELISA. Age-matched and sex-matched healthy volunteers were used as controls. Highly significant differences were found in serum levels of VEGF between SSc patients and healthy controls, whereas no differences could be detected for endostatin and basic fibroblast growth factor. Significantly higher levels of VEGF were detected in patients with Scl-70 autoantibodies and in patients with diffuse SSc. Patients with pre-SSc and short disease duration showed significant higher levels of VEGF than healthy controls, indicating that elevated serum levels of VEGF are a feature of the earliest disease stages. Patients without fingertip ulcers were found to have higher levels of VEGF than patients with fingertip ulcers. Levels of endostatin were associated with the presence of giant capillaries in nailfold capillaroscopy, but not with any other clinical parameter. The results show that the concentration of VEGF is already increased in the serum of SSc patients at the earliest stages of the disease. VEGF appears to be protective against ischemic manifestations when concentrations of VEGF exceed a certain threshold level.
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PMID:Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. 1245 14

The anti-angiogenic activity of endostatin (ES) depends on interactions with heparan sulfate (HS). In the present study, intact HS chains of >/=15 kDa bound quantitatively to ES whereas N-sulfated HS decasaccharides, with affinity for several fibroblast growth factor (FGF) species, failed to bind. Instead, ES-binding oligosaccharides composed of mixed N-sulfated and N-acetylated disaccharide units were isolated from pig intestinal HS. A 10/12mer ES-binding epitope was identified, with two N-sulfated regions separated by at least one N-acetylated glucosamine unit (SAS-domain). Cleavage at the N-acetylation site disrupted ES binding. These findings point to interaction between discontinuous sulfated domains in HS and arginine clusters at the ES surface. The inhibitory effect of ES on vascular endothelial growth factor-induced endothelial cell migration was blocked by the ES-binding SAS-domains and by heparin oligosaccharides (12mers) similar in length to the ES-binding SAS-domains, but not by 6mers capable of FGF binding. We propose that SAS-domains modulate the biological activities of ES and other protein ligands with extended HS-binding sites. The results provide a rational explanation for the preferential interaction of ES with certain HS proteoglycan species.
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PMID:Role of heparan sulfate domain organization in endostatin inhibition of endothelial cell function. 1245 37

Neovastat (AE-941), a naturally occurring multifunctional antiangiogenic agent, has been shown to inhibit key components of the angiogenic process, including matrix metalloproteinases and vascular endothelial growth factor-mediated signaling events. In this study, we report the presence of a proapoptotic activity within this compound. Neovastat treatment of bovine aortic endothelial cells caused cell death with characteristics of apoptosis, including chromatin condensation and DNA fragmentation. Neovastat markedly induced caspase-3, caspase-8, and caspase-9 activities, at similar levels to those measured in cells treated with tumor necrosis factor-alpha. Activation of caspases by Neovastat appears to be essential for its proapoptotic effects because all apoptotic features were blocked by zVAD-fmk, a broad-spectrum caspase inhibitor. The activation of caspases was correlated with the cleavage of the nuclear substrate poly(ADP-ribose) polymerase, and by a concomitant release of cytochrome c from mitochondria to the cytoplasm. Neovastat-induced apoptosis appears to be specific to endothelial cells because treatment of other cell types such as U-87, COS-7, NIH-3T3, and SW1353 did not result in increased caspase-3 activity. These results demonstrate that Neovastat contains a proapoptotic factor that specifically induces the activation of caspases in endothelial cells and the resulting apoptosis of these cells.
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PMID:The antiangiogenic agent Neovastat (AE-941) induces endothelial cell apoptosis. 1249 12

Angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Its inhibition may be a valuable new approach to cancer therapy. Avascular tumors are severely restricted in their growth potential because of the lack of a blood supply. For tumors to develop in size and metastatic potential they must make an "angiogenic switch" through perturbing the local balance of proangiogenic and antiangiogenic factors. Frequently, tumors overexpress proangiogenic factors, such as vascular endothelial growth factor, allowing them to make this angiogenic switch. Two strategies used in the development of antiangiogenic agents involve the inhibition of proangiogenic factors (eg, anti-vascular endothelial growth factor monoclonal antibodies) as well as therapy with endogenous inhibitors of angiogenesis, such as endostatin and angiostatin. Therapy with endogenous angiogenic inhibitors such as endostatin and angiostatin may reverse the angiogenic switch preventing growth of tumor vasculature. Preclinical studies have shown that endostatin effectively inhibits tumor growth and shrinks existing tumor blood vessels. Phase 1 clinical trials of endostatin and angiostatin are ongoing, and preliminary results show minimal toxicities.
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PMID:Role of angiogenesis in tumor growth and metastasis. 1251 34


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