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)

The essential role of angiogenesis in tumor growth and metastasis is well established. The key mediator of angiogenesis, vascular endothelial growth factor (VEGF), is a rational target for novel therapy. High VEGF levels correlate positively with reduced overall survival (OS) and relapse-free survival. Several molecular targeted agents that inhibit VEGF or its receptors are currently in late-stage development or available for the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Bevacizumab is a humanized monoclonal antibody against VEGF that has proven efficacy when combined with different chemotherapy regimens. In the pivotal US phase III trial (E4599) combining bevacizumab with carboplatin/paclitaxel, significantly improved clinical outcomes were observed in terms of OS, progression-free survival (PFS), and response rate (RRs). Although the phase III AVAiL (Avastin in Lung Cancer) trial (BO17704) combining bevacizumab with cisplatin/gemcitabine also showed improved outcomes in terms of PFS and RR, OS data is immature. Bevacizumab is the first agent to improve clinical outcomes when combined with doublet chemotherapy and administered until disease progression. Herein, key clinical data from trials of antiangiogenic agents in the first-line treatment of NSCLC are discussed, with a focus on bevacizumab, currently the only approved antiangiogenic agent for the treatment of NSCLC. The optimal integration of these agents into current and future first-line treatment regimens will be discussed, stressing the importance of therapeutic administration until disease progression. The promising activity of antiangiogenic agents in the advanced disease setting, allied with growing understanding of their novel modes of action, holds therapeutic promise for their future application in early-stage disease.
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PMID:New options for integrating antiangiogenic therapy and platinum-based first-line chemotherapy for advanced non-small-cell lung cancer. 1941 23

The hallmark radiological finding in metastatic brain disease is multiple enhancing lesions. We report a case of metastatic lung cancer to the brain with a lack of contrast enhancement. We believe that this unusual finding is due to inadvertent "treatment" of the metastases with the antiangiogenic agent bevacizumab (Avastin).
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PMID:Nonenhancing brain metastases. 1949 Apr 1

One of the most significant developments in medical oncology practice has been the approval of various antiangiogenic drugs for the treatment of a number of different malignancies. These drugs include bevacizumab (Avastin), the anti-VEGF monoclonal antibody. Thus far, bevacizumab appears to induce clinical benefit in patients who have advanced metastatic disease only or primarily when it is combined with conventional chemotherapy. The reasons for the chemo-enhancing effects of bevacizumab are unknown, and this is a subject that we have been actively studying along with additional ways that antiangiogenic drugs may be combined with chemotherapy. In this respect, we have focused much of our effort on metronomic low dose chemotherapy. We have been studying the hypothesis that some chemotherapy drugs at maximum tolerated doses or other cytotoxic- like drugs such as acute "vascular disrupting agents" (VDAs) can cause an acute mobilization of proangiogenic cells from the bone marrow which home to and colonize the treated tumors, thus accelerating their recovery. These cells include endothelial progenitor cells. This systemic process can be largely blocked by a targeted antiangiogenic drug, e.g. anti-VEGFR-2 antibodies. In addition, metronomic chemotherapy, i.e., close regular administration of chemotherapy drugs at low non-toxic doses with no breaks, over prolonged periods of time not only prevents the acute CEP bone marrow response, but can even target the cells. This potential antiangiogenic effect of metronomic chemotherapy can also be boosted by combination with a targeted antiangiogenic agent. Treatment combinations of metronomic chemotherapy and an antiangiogenic drug have moved into phase II clinical trial testing with particularly encouraging results thus far reported in metastatic breast and recurrent ovarian cancer. Oral chemotherapy drugs such as cyclophosphamide (CTX), methotrexate are the main chemotherapeutics used for such trials. Oral 5-FU prodrugs such as UFT would also appear to be highly suitable based on long term adjuvant therapy studies in patients. Recent preclinical results using metronomic cyclophosphamide and metronomic UFT in models of advanced metastatic breast cancer suggest that this type of combination might be particularly promising for metronomic chemotherapy in this indication, particularly when combined with a targeted antiangiogenic drug.
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PMID:Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs. 1974 37

Angiogenesis is essential for normal tissue and even more so for solid malignancies. At present, inhibition of tumor angiogenesis is a major focus of anticancer drug development. Bevacizumab, a humanized antibody against VEGF, was the first antiangiogenic agent to be approved for advanced non-small cell lung cancer, breast cancer and colorectal cancer. The most commonly observed adverse events are hypertension, proteinuria, bleeding and thrombosis. Sunitinib, a small molecule blocking intracellular VEGF, KIT, Flt3 and PDGF receptors, which regulate angiogenesis and cell growth, is approved for the treatment of advanced renal cell cancer (RCC) and malignant gastrointestinal stromal tumor. The most frequent adverse events include hand-foot syndrome, stomatitis, diarrhea, fatigue, hypothyroidism and hypertension. Sorafenib, an oral multikinase inhibitor, is approved for the second-line treatment of advanced RCC and upfront treatment of advanced hepatocellular carcinoma. Most common adverse events with sorafenib are dermatologic (hand-foot skin reaction, rash, desquamation), fatigue, diarrhea, nausea, hypothyroidism and hypertension. More recently, cardiovascular toxicity has increasingly been recognized as a potential adverse event associated with sunitinib and sorafenib treatment. Elderly patients are at increased risk of thromboembolic events when receiving bevacizumab, and potentially for cardiac dysfunction when receiving sunitinib or sorafenib. The safety of antiangiogenic drugs is of special concern when taking these agents for longer-term adjuvant or maintenance treatment. Furthermore, newer investigational antiangiogenic drugs are briefly reviewed.
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PMID:Antiangiogenic drugs in oncology: a focus on drug safety and the elderly - a mini-review. 1994 Apr 66

Bevacizumab is a humanized monoclonal antibody that was the first FDA approved therapy designed to inhibit angiogenesis. This paper will review the mechanism of action and clinical role of this antiangiogenic agent.
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PMID:Bevacizumab (Avastin). 2003 32

Previous studies have shown that a single point mutation in endostatin at position 125 (P125A) can improve the biological activity of endostatin. Addition of an integrin-targeting moiety, R-G-D, resulted in better localization to tumor vasculature and improved the antiangiogenic activity of endostatin. Because endostatin has relatively shorter serum half-life, frequent dosing was required for inhibiting tumor growth. In our study, we have genetically fused RGD-P125A-endostatin to Fc of IgG4 isotype and evaluated its antiangiogenic and antitumor effects in athymic mice. Two genetic constructs were made, RGD-P125A-endostatin-Fc (RE-Fc) and P125A-endostatin-RGD-Fc (ER-Fc). Both constructs were cloned and expressed in mammalian cells. Purified fusion proteins inhibited endothelial cell migration and proliferation better than yeast-derived P125A-endostatin. Both RE-Fc and ER-Fc inhibited ovarian cancer growth and were found to be as effective as Bevacizumab treatment. Fusion protein showed marked increased half-life. Combination treatment with Bevacizumab and ER-Fc showed additive inhibition of ovarian cancer growth. These studies demonstrate that genetic fusion with human IgG4-Fc increases the half-life of P125A-endostatin and can be used along with Bevacizumab to improve antiangiogenic and antitumor activities.
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PMID:Inhibition of ovarian cancer by RGD-P125A-endostatin-Fc fusion proteins. 2122 21

The main factor involved in neovascularization of ectopic endometrial tissue in endometriosis is the vascular endothelial growth factor (VEGF), which is produced both by the endometrial implant and by peritoneal macrophages. On the other hand, bevacizumab is an antiangiogenic agent used in the treatment of different tumors, like colorectal, pulmonary, and recently mammary. We evaluated the effect of the inhibition of VEGF activity with bevacizumab (Avastin) on ectopic endometrial growth in a murine model of endometriosis. Two months old female BALB/c mice had surgery performed to induce endometriotic-like lesions. Treatment with bevacizumab started on post-surgery day 15 and continued during 2 weeks. Then, animals were sacrificed, peritoneal fluid was collected, and endometriotic-like lesions were counted, measured, and removed. Cell proliferation, vascular density, and apoptosis were assessed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), immunohistochemistry for CD34, and Terminal Deoxynucleotidil Transferase-Mediated dUTP Nick End Labeling (TUNEL), respectively. Vascular endothelial growth factor levels were evaluated in the peritoneal fluid by enzyme-linked immunoassay (ELISA). Treatment with bevacizumab significantly inhibited endometriotic lesion development (P < .05). Consistently, bevacizumab significantly inhibited cell proliferation in lesions (P < .01), reduced vascular density (P < .001), as well as increased the apoptotic cell percentage (P < .001). In addition, bevacizumab reduced VEGF levels in peritoneal fluid of endometriosis-induced animals (P < .05). In conclusion, this study suggests a direct effect of bevacizumab on the reduction of endometrial implant growth and supports further research on VEGF inhibition as a novel therapeutic modality in endometriosis.
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PMID:Effect of vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis. 2126 64

Early monitoring of response to treatment is one of the cornerstones of personalized treatment. As new and often expensive targeted therapies, which are tumoristatic rather than tumoricidal, become available, new demands are posed on response assessment. Bevacizumab, an antiangiogenic agent causing normalization of the tumor microvasculature, potentiates the effect of cytotoxic agents on colorectal liver metastases. It is known that assessment of glucose metabolism by (dynamic) positron emission tomography using [(18)F]-2-fluoro-2-deoxy-D-glucose ((18)F-FDG PET) can be used as an early surrogate endpoint to determine treatment efficacy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to quantify functional tumor vasculature (permeability, vascular surface area). Here, we describe the response of colorectal liver metastases to cytotoxic regimens including bevacizumab using both (18)F-FDG PET and DCE-MRI in 2 cases. In both cases, a large reduction in glucose metabolic rate and functional tumor vasculature are observed after 3 treatment cycles.
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PMID:Vascular and metabolic response to bevacizumab-containing regimens in two patients with colorectal liver metastases measured by dynamic contrast-enhanced MRI and dynamic 18F-FDG-PET. 2160 27

Over the last decades, various new agents have been developed for the treatment of metastatic breast cancer and overall survival of these patients has increased. The role of chemotherapy in the treatment of metastatic breast cancer is well established. Bevacizumab is a potent antiangiogenic agent active in many solid tumors. Three randomised clinical trials (E2100, AVADO and RIBBON I) proved the benefit of chemotherapy, especially a combination of taxanes and bevacizumab, as the first line treatment of metastatic breast cancer. The combination improved patient progression-free survival in all trials with no impact on the known toxic effects of taxanes. This may be a potent treatment option particularly for patients with triple negative breast cancer, and a potentially less toxic alternative to combination chemotherapy.
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PMID:[Avastin in the treatment of breast cancer]. 2164 64

Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), was the first angiogenesis inhibitor approved for the first-line treatment of metastatic colorectal cancer in combination with intravenous fluorouracil-based chemotherapy. Two major cohort studies--BRiTE and BEAT--reported a 2% incidence of bowel perforation, which remains a rare, but serious, complication of bevacizumab treatment. Late anastomotic complications, arising > 3 months after surgery, are emerging occurrences that may be associated with bowel perforation. We report here on such a case caused by pazopanib, a new antiangiogenic agent, and also include a review of the published cases in the literature (n = 23) and an analysis of their management. Proctectomy was the initial surgery in 17 patients (74%) with rectal cancer, and 13 of these patients had undergone adjuvant radiation prior to surgery. The majority (84%) of the complications occurred with antiangiogenic treatment after a mean number of four cycles. Patients' management was invariably associated with withdrawal of the antiangiogenic agent, together with conservative treatment in 14 patients (66%).
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PMID:Late anastomotic colonic dehiscence due to antiangiogenic treatment, a specific drug-class complication requiring specific treatment: an example of pazopanib complication. 2180 88


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