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)

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

Neovascularization is increasingly recognized as an important factor in the pathogenesis of hematologic malignancies as well as solid tumors. The complex interactions between several cell types and numerous cytokine mediators suggest the involvement of autocrine and paracrine signaling mechanisms. Vascular endothelial growth factor (VEGF) in particular is critical to both stimulation of leukemic growth and proliferation of endothelial cells. Tyrosine kinase receptors specific for certain growth factors represent attractive target molecules for anticancer therapy. SU5416 is a competitive inhibitor of VEGF receptor subtypes VEGFR-1 and VEGFR-2 and stem cell factor receptor c-kit. Preclinical evidence shows that SU5416 effectively inhibits VEGF-induced endothelial cell proliferation and slows growth of subcutaneous solid tumor xenografts. This agent is in late-stage clinical trials in patients with solid tumors, and a Phase 2 study was recently initiated to evaluate its utility in the treatment of acute myeloid leukemia. In this Phase 2 study, investigators are seeking to determine the response rate to the antiangiogenic agent SU5416. Translational research in this study is intended to aid our understanding of the precise mechanisms by which SU5416 affects acute myeloid leukemia cells and the bone marrow microenvironment.
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PMID:Role of angiogenesis inhibitors in acute myeloid leukemia. 1177 83

Angiogenesis is a crucial event in the survival and progression of solid tumors. To determine whether angiogenesis in acute myeloid leukemia (AML) is an intrinsic property of leukemic cells, the vascularity of bone marrow biopsies was determined. Bone marrow vascularity in newly diagnosed or post-chemotherapy AML patients was increased 4-fold (P < 0.01) and 8.7-fold (P < 0.01), respectively, relative to controls. Vascular endothelial growth factor (VEGF) expression by AML blast cells was assessed by immunohistochemistry, and bone marrow cell supernatants were assayed for secretion of VEGF, fibroblast growth factor-2 (FGF-2), and endostatin by enzyme-linked immunosorbent assay. Diffuse cytoplasmic and strong extracellular VEGF immunoreactivity was seen in bone marrow aspirates from AML patients, but not controls. In contrast, there was no difference in the levels of VEGF, FGF-2, and endostatin secreted by mononuclear cells cultured from bone marrows of AML patients compared to normal controls following two days of culture in vitro. Total angiogenic potential of bone marrow cell supernatants was assessed by endothelial sprouting in vitro and by a chick chorioallantoic membrane assay. No differences were found between 2-day conditioned medium from normal and AML bone marrow mononuclear cells in either assay. Our data show a discrepancy between bone marrow vascularity and VEGF expression in vivo and VEGF expression and angiogenesis from 2-day conditioned medium ex vivo. This suggests that angiogenesis in AML likely represents a response to microenvironmental factors in vivo, rather than being an intrinsic property of leukemic cells.
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PMID:Role of the microenvironment in promoting angiogenesis in acute myeloid leukemia. 1199 78

In recent decades, radiation research has concentrated primarily on the cancer cell compartment. Much less is known about the effect of ionizing radiation on the endothelial cell compartment and the complex interaction between tumor cells and their microenvironment. Here we report that ionizing radiation is a potent antiangiogenic agent that inhibits endothelial cell survival, proliferation, tube formation and invasion. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor were able to reduce the radiosensitivity of endothelial cells. Yet, it is also found that radiation induces angiogenic factor production by tumor cells that can be abrogated by the addition of antiangiogenic agents. Receptor tyrosine kinase inhibitors of Flk-1/KDR/VEGFR2, FGFR1 and PDGFR beta, SU5416, and SU6668 enhanced the antiangiogenic effects of direct radiation of the endothelial cells. In a coculture system of PC3 prostate cancer cells and endothelial cells, isolated irradiation of the PC3 cells enhanced endothelial cell invasiveness through a Matrigel matrix, which was inhibited by SU5416 and SU6668. Furthermore, ionizing radiation up-regulated VEGF and basic fibroblast growth factor in PC3 cells and VEGFR2 in endothelial cells. Together these findings suggest a radiation-inducible protective role for tumor cells in the support of their associated vasculature that may be down-regulated by coadministration of angiogenesis inhibitors. These results rationalize concurrent administration of angiogenesis inhibitors and radiotherapy in cancer treatment.
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PMID:SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro. 1283 71

Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, and endostatin directly antagonises the biological effects of VEGF. The maintenance of pulmonary endothelial cells is also thought to depend upon the local balance of VEGF and endostatin in the lung. Therefore, this study was designed to determine whether there is an imbalance between VEGF and endostatin levels in patients with pulmonary emphysema. VEGF and endostatin levels were simultaneously measured from 25 emphysema patients and 12 normal control subjects, and their correlation and balance in induced sputum was evaluated. VEGF levels in induced sputum were significantly lower in emphysema patients (854 +/- 307 pg x mL(-1)) than in normal controls (1,791 +/- 1,192 pg x mL(-1)). In contrast, there was no significant difference in endostatin levels among the two groups. Therefore, the ratio of VEGF to endostatin levels was markedly lower in emphysema patients (4.5 +/- 1.8) than in normal controls (8.1 +/- 2.6). Moreover, VEGF levels were correlated with endostatin levels in normal controls but not in emphysema patients. In addition, the ratio of VEGF to endostatin levels was correlated with forced expiratory volume in one second (FEV1), FEV1/forced vital capacity and carbon monoxide diffusing capacity of the lung in emphysema patients. The findings in this study suggest that there is an imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from emphysema patients.
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PMID:Imbalance between vascular endothelial growth factor and endostatin in emphysema. 1458 12

Vascular endothelial growth factor (VEGF), an established angiogenesis factor, is expressed in allografts undergoing rejection, but its function in the rejection process has not been defined. Here, we initially determined that VEGF is functional in the trafficking of human T cells into skin allografts in vivo in the humanized SCID mouse. In vitro, we found that VEGF enhanced endothelial cell expression of the chemokines monocyte chemoattractant protein 1 and IL-8, and in combination with IFN-gamma synergistically induced endothelial cell production of the potent T cell chemoattractant IFN-inducible protein-10 (IP-10). Treatment of BALB/c (H-2d) recipients of fully MHC-mismatched C57BL/6 (H-2b) donor hearts with anti-VEGF markedly inhibited T cell infiltration of allografts and acute rejection. Anti-VEGF failed to inhibit T cell activation responses in vivo, but inhibited intragraft expression of several endothelial cell adhesion molecules and chemokines, including IP-10. In addition, whereas VEGF expression was increased, neovascularization was not associated with acute rejection, and treatment of allograft recipients with the angiogenesis inhibitor endostatin failed to inhibit leukocyte infiltration of the grafts. Thus, VEGF appears to be functional in acute allograft rejection via its effects on leukocyte trafficking. Together, these observations provide mechanistic insight into the proinflammatory function of VEGF in immunity.
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PMID:Proinflammatory functions of vascular endothelial growth factor in alloimmunity. 1466 Jul 42

Human endostatin has an internal Asn-Gly-Arg (NGR) motif at position 126-128 following a proline at position 125. Asn-Gly-Arg-containing peptides have been shown to target tumour vasculature and inhibit aminopeptidase N activity. We previously compared the in vitro and in vivo biological activities of native endostatin and endostatin with a proline to alanine mutation (P125A-endostatin). P125A-endostatin exhibited greater inhibition of both endothelial cell proliferation and human ovarian cancer growth compared to native endostatin. Here we explore further the effects on biological activity of the P125A mutation, and show that aminopeptidase N is not involved. To determine whether the increased biological activity of the mutant was due to unmasking of downstream NGR-sequence, effect of endostatin on aminopeptidase N activity was investigated. Neither the native nor the P125A-endostatin inhibited aminopeptidase N. However, synthetic peptides consisting of the S118-T131 region of endostatin inhibited aminopeptidase N. These results suggest that the internal NGR site in native or mutant endostatin is not accessible to aminopeptidase N, and that this activity is not involved in the enhanced biological activity of the P125A form. P125A-endostatin bound to endothelial cells more efficiently than native endostatin and exhibited greater inhibition of not only proliferation but also migration of endothelial cells. P125A-endostatin also localised into tumour tissue to a higher degree than the native protein, and displayed greater inhibition of growth of colon cancer in athymic mice. Both proteins inhibited tumour cell-induced angiogenesis effectively. Real-time PCR analysis showed that both native and P125A-endostatin decreased expression of key proangiogenic growth factors. Vascular endothelial growth factor and angiopoietin 1 were downregulated more by the mutant. These studies suggest that the region around P125 can be modified to improve the biological activity of endostatin.
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PMID:Improved biological activity of a mutant endostatin containing a single amino-acid substitution. 1508 96

Angiogenesis is essential for wound repair after surgical trauma. Vascular endothelial growth factor (VEGF) and endostatin are endogenous angiogenic factors involved in the initiation and completion of angiogenesis. The aim of this study was to examine the local and systemic VEGF and endostatin profiles in patients undergoing surgery for benign and malignant breast processes. A total of 16 patients with or without cancer underwent breast surgery. Group I: eight patients with primary breast cancer underwent a simple or radical mastectomy according to Madden including dissection of axillary lymph nodes. Group II: eight healthy female-to-male transsexuals underwent subcutaneous mastectomy. VEGF and endostatin levels in plasma and wound fluid were determined. In both groups VEGF levels in wound fluid were significantly higher compared to postoperative plasma levels, whereas wound fluid endostatin levels were lower than plasma levels and decreased progressively after surgery. In both groups plasma VEGF and endostatin levels did not change significantly before and after surgery. The local VEGF increase and endostatin decrease observed immediately after surgery appears to be a physiological response to operative trauma, which can be studied more profoundly in locally generated fluid than in blood. This process did not seem to be influenced by the type of process (cancerous or non-cancerous) involved in the surgical intervention.
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PMID:VEGF and endostatin levels in wound fluid and plasma after breast surgery. 1516 93

Vascular endothelial growth factor (VEGF) has been shown to play an important role during endochondral bone formation in hypertrophic cartilage remodeling, ossification, and angiogenesis, but it is not expressed in normal adult articular cartilage. Thyroid cartilage undergoes only partial ossification beginning at the age of about 20. Because it never completely ossifies, we investigated a possible role of VEGF and its receptors (VEGFRs) as well as the angiogenetic inhibitor endostatin in this permanent cartilage. In analysis of cartilage samples from all specimens evaluated, VEGF121 and VEGF165 were identified as the only VEGF splice forms expressed. In addition to VEGF, VEGFR-2 (kinase domain region/fetal liver kinase 1), but not VEGFR-1 (fms-like tyrosine kinase 1), was detectable by RT-PCR in cartilage. However, VEGFR-2 expression was only detectable up to the age of 19 years. Deposition of VEGF and VEGFR was confirmed by immunohistochemistry. VEGF concentrations measured by ELISA in thyroid cartilage increased with age in males but decreased in females. Endostatin concentrations measured by ELISA in thyroid cartilage were three times lower than in articular cartilage and showed no change with age, either in females or males. VEGF was immunostained within the intra- and pericellular matrices of some but not all chondrocytes. Thus, apart from its production in hypertrophic chondrocytes of growth plates, VEGF is also produced in single chondrocytes of thyroid cartilage. The data allow us to speculate that thyroid cartilage persists in an embryological state until it has reached its final size. After reaching its final size at the end of the second decade, VEGFR-2 is downregulated and ossification starts in the posterior part of the thyroid cartilage, proceeding ventrally. Both proteins, VEGF121 and VEGF165, should contribute to this process. VEGF concentration is high and changes in an age-related and sex-specific manner. Therefore, we postulate that VEGF is at least one of the key factors that is important for the lifelong ossification in thyroid cartilage.
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PMID:VEGF expression in adult permanent thyroid cartilage: implications for lack of cartilage ossification. 1526 7

Many degenerative processes in the skeletal system are induced by mechanical overload. Osteoarthritis and spontaneous tendon ruptures are two examples of mechanically influenced diseases. Incubator-housed compression apparatuses and cyclic strain chambers are adequate models to investigate the cellular processes. Recent studies have shown that growth factors are involved in the transduction pathways of mechanical overload leading to tissue degradation. Vascular endothelial growth factor (VEGF) is a dimerized, 45 kDa peptide that normally attracts endothelial cells in wound healing. VEGF can be detected in the superficial zone of the tibial plateau in osteoarthritic (OA) patients with degenerative changes but not in healthy articular cartilage. Blood vessels are only rarely observed in OA cartilage suggesting that there are other roles for VEGF in cartilage. VEGF is also detectable in ruptured but not in normal tendons. The mechanically induced expression of VEGF in avascular tissues like articular cartilage or fibrocartilage of contact areas from gliding tendons initiates degenerative processes. Chondrocytes from OA cartilage also express the VEGF receptor 2. In vitro assays have shown that VEGF binds the VEGFR-2 leading to a phosphorylation of MAP kinases (ERK1/2) with subsequent transcription factor accumulation (activator protein 1 = AP-1). One of the antagonists of VEGF is endostatin. Endostatin, a fragment of collagen type XVIII, is expressed in avascular tissues and has the potency to decrease VEGF induced effects (ERK1/2 phosphorylation). The increase in matrix metalloproteinase (MMP) production and the decrease in tissue inhibitor metalloproteinase (TIMP) synthesis is a result of the signal transduction cascade activation. MMPs participate in the degradation processes of osteoarthritis whereas TIMPs are inhibitors of the MMPs. Taken together mechanically induced VEGF is involved in the destruction and endostatin in the maintenance of avascular tissues of the bone and joint system.
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PMID:The influence of biomechanical parameters on the expression of VEGF and endostatin in the bone and joint system. 1632 Aug 26


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