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 process of new capillary formations from previously existing mature vessels in healthy individuals has been mainly studied during cycles of the female reproductive tract. This new capillary formation, known as angiogenesis is related to endogenous regulators that both stimulates or inhibits it. Knowledge on the role of both stimulators and inhibitors under physiological and pathological conditions accentuates a main role of VEGF, FGF, angiogenin and angiopoietics among the formers; and main role of angiostatin and endostatin among the latters. In recent years, angiogenesis in the ovaries that leads to follicular and luteal growth and development has been extensively studied. Whether a number of endogenous stimulators and inhibitors have been identified, the molecular link between the endocrine and vascular system is not fully understood. Therefore, efforts to formulate questions that need answers must be made.
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PMID:[Angiogenesis in reproductive physiology. Follicular development, formation and maintenance of the corpus luteum]. 1191 46

In cell culture, the compound 317615 2HCl, a potent inhibitor of VEGF-stimulated HUVEC proliferation, was not very effective against MX-1 breast cancer cells (IC50= 8.1 microM) or SKOV-3 ovarian carcinoma cells (IC50 = 9.5 microM). Exposure to combinations of paclitaxel or carboplatin and 317615 x 2HCl with MX-1 cells in culture resulted in cell survival that reflected primarily additivity of the two agents. Exposure of SKOV-3 cells to paclitaxel or carboplatin along with 317615 2HCl resulted in cell survivals that reflected additivity of 317615 x 2HCl with paclitaxel and greater-than-additive cytotoxicity with carboplatin. Administration of 317615 x 2HCI orally twice daily to nude mice bearing subcutaneous MX-1 tumors or SKOV-3 tumors resulted in a decreased number of intratumoral vessels as determined by CD31 and CD105 staining with decreases of 35% and 43% in MX-1 tumors and 60% and 75% in SKOV-3 tumors, respectively. 317615 x 2HCl was an active antitumor agent against the MX-1 xenograft and increased the tumor growth delay produced by paclitaxel by 1.7-fold and the tumor growth delay produced by carboplatin by 3.8-fold. Administration of 317615 x 2HCl also increased the tumor growth delay produced by fractionated radiation therapy in the MX-1 tumor. Treatment with 317615 x 2HCl alone increased the lifespan of animals bearing intraperitoneal SKOV-3 xenografts by 1.9 fold compared with untreated control animals. The combination of paclitaxel and 317615 x 2HCl resulted in 100% 120-day survival of SKOV-3 bearing animals. Administration of 317615 x 2HCl along with carboplatin to animals bearing the SKOV-3 tumor produced a 1.8-fold increase in lifespan compared with carboplatin alone. 317615 x 2HCl is a promising new antiangiogenic agent that is in early phase clinical testing.
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PMID:Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human breast cancer and ovarian cancer xenografts. 1220 87

It has become increasingly clear that definitive tests for angiogenesis require in vivo assays. Recently, the Matrigel plug assay has become the method of choice for many studies involving in vivo testing for angiogenesis. In this assay, test angiogenesis-inducing compounds such as bFGF or tumor cells are introduced into cold liquid Matrigel which, after subcutaneous injection, solidifies and permits penetration by host cells and the formation of new blood vessels. Assessment of angiogenesis in the Matrigel plug is achieved either by measuring hemoglobin or by scoring selected regions of histological sections for vascular density. We now describe a modification of the Matrigel plug assay which permits a more precise visualization of the angiogenic reaction, provides directional information, requires no histological analysis, and lends itself to photographic documentation and image analysis protocols. We illustrate the assay by describing dose- and time-dependent responses to tumors of murine and human origin, to angiogenesis-inducing factors such as bFGF (FGF-2) and VEGF and to anti-angiogenic agents such as endostatin. The method has been used as well to demonstrate blood vessel recruitment by embryonic chick aortic arch rudiments. Additionally it has been able to detect strain-dependent differences in susceptibility to angiogenic stimulation.
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PMID:The sponge/Matrigel angiogenesis assay. 1254 62

In 2002, new developments in anti-angiogenic strategies encompassed two main aspects. Firstly, essential improvements were made in the field of methodology : novel techniques permitted to measure directly on patients the biological effects induced by anti-angiogenic treatments in the course of clinical trials. Secondly, results of the first phase I trials of endostatin, one of the most awaited anti-angiogenic drugs, were published. These studies proved that endostatin was not toxic and that doses equivalent to the one effective in animals could safely be used in man, but efficacy results were not up to expectations. On the other hand, treatment targeting the VEGF pathway, and especially humanised anti-VEGF monoclonal antibody, had promising results. Further clinical trials are needed to gain clear insight into the precise role of those promising strategies for the management of solid tumours.
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PMID:[Clinical development of anti-angiogenic agents in 2002]. 1260

Measurement of tumor angiogenesis to predict and/or to assess the efficacy of antiangiogenic therapies is mainly based on the evaluation of microvessel density (MVD). We developed a novel flow cytometry procedure to measure circulating endothelial cells (CECs) and circulating endothelial cells progenitors (CECPs) in either preclinical and clinical studies. Preclinical studies were performed on an animal model of human lymphoma. A trend toward higher CECs values was observed on day 7 and 14 after transplant, and differences vs controls were highly significant on day 21 (p = 0.0061). A strong correlation was found between CECs and tumor volume (r = 0.942, p = 0.004) and between CECs and tumor-generated VEGF (r = 0.669, p = 0.02). In mice given cyclophosphamide, most of circulating apoptotic cells were hematopoietic and not endothelial. Conversely, in mice given endostatin, all of the increase in apoptotic cells was in the endothelial cell compartment. In a parallel study, we looked for CECs in the peripheral blood of 20 healthy controls and 76 newly diagnosed cancer patients by means of four-color flow cytometry. In breast cancer (n = 46) and lymphoma (n = 30) patients, both resting and activated CECs were increased by 5 fold (P < 0.0008 vs control). CECs significantly correlated with plasma levels of VCAM-1 and VEGF. Resting and activated CECs were similar to healthy controls in 7 lymphoma patients achieving complete remission after chemotherapy, and activated CECs were found to decrease in 13 breast cancer patients evaluated before and 24h after quadrantectomy. In conclusion, our findings indicate a close relation between CEC increase and tumor progression, and support CECs evaluation as a clinically relevant, non invasive angiogenesis marker. Furthermore, this assay offers insight into anti-angiogenic activity of different drugs.
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PMID:Circulating endothelial cells as a novel marker of angiogenesis. 1267 13

Inhibition of angiogenesis is an important new modality for cancer treatment. 2-methoxyestradiol (2ME2) is a novel antitumor and antiangiogenic agent, currently in clinical trials, whose molecular mechanism of action remains unclear. Herein, we report that 2ME2 inhibits tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) in vivo. Mechanistically, we found that 2ME2 downregulates hypoxia-inducible factor-1 (HIF) at the posttranscriptional level and inhibits HIF-1-induced transcriptional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-alpha downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton and inhibition of angiogenesis.
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PMID:2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. 1272 62

Despite much enthusiasm, no clear clinical benefit to any antiangiogenic agent has yet been demonstrated. Phase I trials demonstrate that endostatin, an endothelial cell toxin, can be administered safely, but no obvious anti-tumor effects were observed. Certain matrix metalloproteinase inhibitors appear ineffective, but later generation inhibitors with less systemic toxicity continue to be investigated. There are occasional responses to thalidomide either singly or in combination, but its pharmacology and mechanism of action remain unclear. A randomized study with the anti-VEGF antibody bevacizumab suggests that VEGF pathway is an important target in renal cell cancer. VEGF receptor tyrosine kinase inhibitors continue to be developed, but one of the first compounds SU5416 has had minimal clinical effects. Clinical trial designs that address the stable disease endpoint should thus be investigated and the randomized discontinuation design has already been tested. Pharmacodynamic markers that reflect antiangiogenic drug effect also need to be developed, but the putative ones, including circulating proangiogenic factors, tumor microvessel density, and dynamic contrast MRI have not yet proven to be useful.
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PMID:Angiogenesis inhibitors in genitourinary cancers. 1285 May 26

Previously we demonstrated that domain 5 (D5) of high-molecular-weight kininogen (HK) inhibits neovascularization in the chicken chorioallantoic membrane (CAM) assay and further found that kallikrein cleaved HK (HKa) inhibited FGF2-and VEGF-induced neovascularization, and thus was antiangiogenic. In this study, we sought to demonstrate whether uncleaved HK stimulates neovascularization and thus is proangiogenic. The chick chorioallantoic membrane was used as an in ovo assay of angiogenesis. Low-molecular-weight kininogen stimulates angiogenesis, indicating that D5 is not involved. Bradykinin stimulates neovascularization equally to HK and LK and is likely to be responsible for the effect of HK. A murine monoclonal antibody to HK (C11C1) also recognizes a similar component in chicken plasma as detected by surface plasmon resonance. Angiogenesis induced by FGF2 and VEGF is inhibited by this monoclonal antibody and is a more potent inhibitor of neovascularization induced by VEGF than an integrin alphavbeta3 antibody (LM 609). Our postulate that C11C1 inhibits the stimulation of angiogenesis by HK was confirmed when either C11C1 or D5 completely inhibited angiogenesis in the CAM induced by HK. Growth of human fibrosarcoma (HT-1080) on the CAM was inhibited by GST-D5 and C11C1. These results indicate HK is proangiogenic probably by releasing bradykinin and that a monoclonal antibody directed to HK could serve as an antiangiogenic agent with a potential for inhibiting tumor angiogenesis and other angiogenesis-mediated disorders.
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PMID:Inhibition of angiogenesis by antibody blocking the action of proangiogenic high-molecular-weight kininogen. 1287 54

Gonadotropins induce ovarian follicle growth that is coincident with increased follicular vasculature, suggesting a role of angiogenesis in follicle development. Functional studies performed in nonhuman primates show that administration of substances that inactivate VEGF block the development and function of preovulatory follicles as demonstrated by histological analysis or hormone measurements. Blockage of function of VEGF receptor 2 (VEGFR-2) alters follicular hormone secretion, suggesting that the intraovarian effect of VEGF might be mediated by this receptor. The specific mechanism by which follicular development was blocked in these previous studies remains unclear, however. Here we characterize the intraovarian role of VEGFR-2 activity on follicular development by choosing a model in which active feedback is absent, the prepuberally hypophysectomized mouse. Hypophysectomy prevents advanced follicle growth and maturation; however, follicle development to the preovulatory stage can be stimulated by administration of gonadotropins. We report that exogenously administered gonadotropins are unable to drive follicle development to the preovulatory stage in the presence of antiangiogenic agent, VEGFR-2-neutralizing Ab's. This inhibition of follicular development is caused by arrests to both angiogenesis and antrum formation. We conclude that the intraovarian VEGF/VEGFR-2 pathway is critical for gonadotropin-dependent angiogenesis and follicular development.
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PMID:Vascular endothelial growth factor receptor 2-mediated angiogenesis is essential for gonadotropin-dependent follicle development. 1295 15

There is no unique formula for angiogenesis. Instead there is a large group of potential participating proteins that interact in complex ways. Depending upon the surrounding cell types and the relative expression levels of angiogenesis-related proteins, the 'angiogenesis cascade' can vary. Therefore, it is valuable to study and compare the role of proteins in several well-characterized vascular beds. The eye provides a useful model system, because it contains several vascular beds sandwiched between avascular tissue. This allows for unequivocal identification and quantitation of new vessels. Retina-specific promoters combined with inducible promoter systems provide a means to regulate the expression of proteins of interest. As a relatively isolated compartment, the eye also provides advantages for gene transfer. By gaining insight regarding the molecular signals involved in various types of ocular angiogenesis, general concepts can emerge that may apply to other settings, including tumor angiogenesis. One concept that has emerged is that despite participation of multiple stimulatory factors for ocular neovascularization, VEGF plays an essential role and interruption of VEGF signaling is an important therapeutic strategy. Another concept is that while most studies have focused on prevention of ocular neovascularization, regression of new vessels is desirable and is achievable with at least three agents, combretastatin A-4 phosphate, pigment epithelium-derived factor, and angiopoietin-2. Finally, endostatin and angiostatin, which have been sources of controversy because of inconsistent results in tumor models, have been shown to have good efficacy when delivered by gene transfer in models of ocular neovascularization. These results provide leads for new ocular treatments and perspective for evaluation of studies of neovascularization in extraocular tissues.
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PMID:Ocular neovascularization: a valuable model system. 1452 78


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