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)

Linomide is a p.o. active antiangiogenic agent that has been demonstrated to be effective in suppressing the in vivo growth of rat and human prostatic cancer xenografts. The present studies were conducted to determine whether the angiogenic molecules, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and basic fibroblast growth factor (bFGF) are expressed in vitro by DU-145, PC-3, TSU-PR1, and LnCaP human prostate cancer cell lines and whether Linomide inhibits the secretion of these angiogenic molecules. Additionally, two different androgen-responsive human prostatic cancer xenograft models (i.e., PC-82 and A-2) were used to determine whether androgen ablation-induced reduction in tumor growth is associated with a reduction in tumor VEGF and/or bFGF levels. These studies demonstrated that both VEGF and bFGF proteins are expressed to different degrees in the human prostatic cancer cell lines. The secretion of VEGF but not bFGF is up-regulated by hypoxia. Linomide is unable to inhibit either basal or hypoxia-induced secretion of VEGF. Linomide also has no effect on secreted bFGF levels. Castration inhibited tumor VEGF but had no effect on bFGF levels in both the androgen-responsive PC-82 and A-2 human prostatic cancers when grown in severe combined immunodeficient mice. When given in combination, castration potentiated the inhibition of tumor growth induced by Linomide alone. This potentiation is not due to a further inhibition in tumor VEGF levels induced by castration. Although both castration and Linomide inhibit angiogenesis, the former accomplishes it by inhibiting VEGF secretion, whereas the latter has multiple effects at several steps in the angiogenic process other than VEGF secretion. Based on their different but complementary mechanisms of action, simultaneous combination of androgen ablation with Linomide enhances the anti-prostatic cancer efficacy compared to either monotherapies alone and warrants testing in humans.
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PMID:Potentiation of the antiangiogenic ability of linomide by androgen ablation involves down-regulation of vascular endothelial growth factor in human androgen-responsive prostatic cancers. 906 70

Angiogenesis, the recruitment of new blood vessels, is an essential component of the metastatic pathway. These vessels provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. For many tumors, the vascular density can provide a prognostic indicator of metastatic potential, with the highly vascular primary tumors having a higher incidence of metastasis than poorly vascular tumors. Tumor angiogenesis is regulated by the production of angiogenic stimulators including members of the fibroblast growth factor and vascular endothelial growth factor families. In addition, tumors may activate angiogenic inhibitors such as angiostatin and endostatin that can modulate angiogenesis both at the primary site and at downstream sites of metastasis. The potential use of these and other natural and synthetic angiogenic inhibitors as anticancer drugs is currently under intense investigation. Such agents may have reduced toxicity and be less likely to generate drug resistance than conventional cytotoxic drugs. Clinical trials are now underway to develop optimum treatment strategies for antiangiogenic agents.
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PMID:Angiogenesis and tumor metastasis. 950 72

Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.
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PMID:Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy. 986 20

Recombinant humanized antivascular endothelial growth factor (rhuMAbVEGF) is a monoclonal IgG1 antibody that is being developed as an antiangiogenic agent for use in treating a variety of solid tumors. Preclinical safety studies included an immunohistochemical tissue cross-reactivity study, in vitro hemolytic potential and blood compatibility studies, and multiple dose toxicity studies. Toxicity studies were conducted in cynomolgus monkey because rhuMAbVEGF is pharmacologically active in this species and does not bind rat or mouse vascular endothelial growth factor (VEGF). Following twice weekly administration of rhuMAbVEGF for 4 or 13 wk, young adult cynomolgus monkeys exhibited physeal dysplasia characterized by a dose-related increase in hypertrophied chondrocytes, subchondral bony plate formation, and inhibition of vascular invasion of the growth plate. In addition, decreased ovarian and uterine weights and an absence of corpora lutea were observed in females receiving 10 and 50 mg/kg/dose in the 13-wk study. Both the physeal and ovarian changes were reversible with cessation of treatment. No other treatment-related effects were observed following rhuMAbVEGF administration at doses up to 50 mg/kg. These findings indicate that VEGF is required for longitudinal bone growth and corpora lutea formation and that rhuMAbVEGF can reversibly inhibit physiologic neovascularization at these sites.
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PMID:Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. 1036 78

Tumors do not grow without inducing a new vessel formation. The postulation of Dr. Folkman in 1971-that tumor growth is angiogenesis-dependent-has been widely accepted, more than two decades later. The question now becomes, "Is it possible to treat cancer by attacking its blood supply?" Many pharmaceutical companies directed their research to antiangiogenic therapy in the past years. Despite increasing knowledge of tumor-induced angiogenesis, the mechanism as to how antiangiogenic agents inhibit new vessel formation remains unknown. Even the mechanisms of two of the most potent preclinical antiangiogenic drugs, angiostatin and endostatin, are still unknown. Many factors are involved in new vessel formation and experimental models are not sophisticated enough to take into account all factors that play a role in spontaneously occurring tumors. Translational research from the clinic to the laboratory is warranted for the discovery of new potent antiangiogenic agents. Our translational angiogenesis research started two years ago, when we hypothesized that circulating concentrations of vascular endothelial growth factor (VEGF), an important angiogenic factor, if initially elevated, would decrease during therapy in cancer patients. Until then, several investigators tried to correlate serum concentrations of VEGF with the prognosis of cancer patients. Fascinatingly, we found a specific pattern of VEGF concentrations that correlated exactly with the platelet counts of these patients during therapy. No relationship with tumor burden was detected, indicating that circulating levels of VEGF are not influenced by tumor cells, but are mainly dependent on platelet contents. In addition, it was shown by others that thrombin activation of platelets causes VEGF release.What then is the role of circulating VEGF carried by platelets? VEGF has been shown to induce permeability, has mitogenic and chemotactic activity on endothelial cells, and also has procoagulatory activity. Platelets play a critical role in wound healing and, if they are activated, they release upon activation, in addition to VEGF, other growth factors that are involved in angiogenesis (e.g., platelet-derived endothelial cell growth factor, thrombospondin, and platelet factor 4). On the other hand, in the clinic it was found that platelet counts have prognostic significance for cancer patients and that coagulation abnormalities are regularly found in cancer patients. In preclinical studies the tumor-platelet interactions have been studied extensively and a relationship between metastasis formation and platelet-tumor interaction has been reported. We are currently investigating whether a specific tumor endothelium-platelet interaction can contribute to tumor-induced angiogenesis.Although these translational studies have no direct impact on clinical cancer therapy, oncologists should be aware of a potential role for platelets in cancer growth. For example, bone marrow-supportive agents, currently used in high-dose chemotherapy, contribute to platelet production and thereby may influence response to therapy. At this time we investigate in our hospital the pretreatment platelet counts in cancer patients, and we are studying how bone marrow-supportive agents during chemotherapy affect these counts in relation to the response to therapy. We would be pleased to learn of your observations.
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PMID:Tumor Growth: A Putative Role for Platelets? 1038 96

We have studied two related proteins that contain a repeated amino acid motif homologous to the anti-angiogenic type 1 repeats of thrombospondin-1 (TSP1). Complete sequence analysis revealed no other similarities with TSP1, but identified unique signal sequences, as well as metalloprotease and disintegrin-like domains in the NH(2) termini. We named these proteins METH-1 and METH-2 due to the novel combination of metalloprotease and thrombospondin domains. Overall amino acid sequence identity between METH-1 and METH-2 is 51. 7%, yet transcript distribution revealed non-overlapping patterns of expression in tissues and cultured cell lines. To characterize these proteins functionally, we isolated full-length cDNAs, produced recombinant protein, and generated antisera to the recombinant proteins. Both METH-1 and METH-2 represent single copy genes, which encode secreted and proteolytically processed proteins. METH proteins suppressed fibroblast growth factor-2-induced vascularization in the cornea pocket assay and inhibited vascular endothelial growth factor-induced angiogenesis in the chorioallantoic membrane assay. Suppression of vessel growth in both assays was considerably greater than that mediated by either thrombospondin-1 or endostatin on a molar basis. Consistent with an endothelial specific response, METH-1 and METH-2 were shown to inhibit endothelial cell proliferation, but not fibroblast or smooth muscle growth. We propose that METH-1 and METH-2 represent a new family of proteins with metalloprotease, disintegrin, and thrombospondin domains. The distinct distribution of each gene product suggests that each has evolved distinct regulatory mechanisms that potentially allow for fine control of activity during distinct physiological and pathological states.
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PMID:METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. 1043 12

Malignant tumours are angiogenesis-dependent diseases. Several experimental studies suggest that primary tumour growth, invasiveness and metastasis require neovascularisation. Tumour-associated angiogenesis is a complex multistep process under the control of positive and negative soluble factors. A mutual stimulation occurs between tumour and endothelial cells by paracrine mechanisms. Angiogenesis is necessary, but not sufficient, as the single event for tumour growth. There is, however, compelling evidence that acquisition of the angiogenic phenotype is a common pathway for tumour progression, and that active angiogenesis is associated with other molecular mechanisms leading to tumour progression. Experimental research suggests that it is possible to block angiogenesis by specific inhibitory agents, and that modulation of angiogenic activity is associated with tumour regression in animals with different types of neoplasia. The more promising angiosuppressive agents for clinical testing are: naturally occurring inhibitors of angiogenesis (angiostatin, endostatin, platelet factor-4 and others), specific inhibitors of endothelial cell growth (TNP-470, thalidomide, interleukin-12 and others), agents neutralising angiogenic peptides (antibodies to fibroblast growth factor or vascular endothelial growth factor, suramin and analogues, tecogalan and others) or their receptors, agents that interfere with vascular basement membrane and extracellular matrix [metalloprotease (MMP) inhibitors, angiostatic steroids and others], antiadhesion molecules antibodies such as antiintegrin alpha v beta 3, and miscellaneous drugs that modulate angiogenesis by diverse mechanisms of action. Antiangiogenic therapy is to be distinguished from vascular targeting. Gene therapy aimed to block neovascularisation is also a feasible anticancer strategy in animals bearing experimental tumours. Antiangiogenic therapy represents one of the more promising new approaches to anticancer therapy and it is already in early clinical trials. Because angiosuppressive therapy is aimed at blocking tumour growth indirectly, through modulation of neovascularisation, antiangiogenic agents need to be developed and evaluated as biological response modifiers. Therefore, adequate and well designed clinical trials should be performed for a proper evaluation of antiangiogenic agents, by determination and monitoring of surrogate markers of angiogenic activity.
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PMID:The rationale and future potential of angiogenesis inhibitors in neoplasia. 1043 27

Endostatin, produced as recombinant protein in human 293-EBNA cells, inhibits the migration of human umbilical vein endothelial cells (HUVECs) in response to vascular endothelial growth factor (VEGF) in a dose-dependent manner and prevents the subcutaneous growth of human renal cell carcinomas in nude mice at concentrations and in doses that are from 1000- to 100 000-fold lower than those previously reported. The inhibition of migration is not affected by mutations which eliminate Zn or heparin binding and inhibition of tumor growth does not depend on Zn binding. The results of the migration assays suggest that endostatin causes a block at one or more steps in VEGF-induced migration, while VEGF in turn can cause a block of the inhibition by endostatin of VEGF-induced migration of HUVECs.
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PMID:Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. 1044 7

A number of clinical studies have demonstrated the prognostic significance of angiogenesis and angiogenic growth factors in solid tumours; however, very little is known about the relevance of these parameters in haematological malignancies. We evaluated circulating levels of angiogenic growth factors and endostatin in 36 non-Hodgkin's lymphoma (NHL) patients. Baseline vascular endothelial growth factor (VEGF) levels of patients in complete remission (CR) after a median follow-up of 21 months were significantly lower than those of patients with progressive disease (P = 0.016). Event-free survival (EFS) rate was significantly higher in patients who had baseline VEGF and basic-fibroblast growth factor (b.FGF) levels below the median values of 147 and 19.5 pg/ml (P = 0.018 and 0.039 by log-rank test, respectively). Conversely, the levels of endostatin, angiogenin and leptin were not different in CR patients compared to relapsed patients and did not correlate with EFS. Our data suggest that b-FGF and, particularly, VEGF might be considered prognostic factors in NHL staging and management.
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PMID:Angiogenic growth factors and endostatin in non-Hodgkin's lymphoma. 1084 4

We conducted a Phase II clinical trial of the antiproliferative, antimetastatic, and antiangiogenic agent carboxyamido-triazole (CAI), using pharmacokinetic assessment to guide drug dosing. Fifteen patients who had stage D2 androgen-independent prostate cancer with soft tissue metastases were enrolled. Because CAI previously had been shown to decrease prostate-specific antigen secretion in vitro, this marker was not used to assess disease status. The dose of CAI used in this study was calculated so that plasma steady-state maximum concentrations between 2.0 and 5.0 microg/ml would be maintained. Following the initial dosage adjustment, 93% (14 of 15) of patients were within the predicted range. Fourteen of 15 patients were evaluable for response. All of the 14 evaluable patients demonstrated progressive disease at approximately 2 months. Twelve patients progressed by computed tomography and or bone scan at 2 months, whereas two patients demonstrated clinical progression at 1.5 and 2 months. One patient was removed from study at 6 weeks due to grade II peripheral neuropathy lasting >1 month. Although no clinical responses were noted, a 27.7% decrease in serum vascular endothelial growth factor concentration was observed. CAI does not possess clinical activity in patients with androgen-independent prostate cancer and soft tissue metastases. Pharmacokinetically guided dosing, although found to be feasible using a Bayesian approach, was not found to be of practical benefit. Although plasma CAI concentrations were maintained within the designated range, grade III toxicity requiring drug discontinuation was still observed.
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PMID:A pharmacokinetically guided Phase II study of carboxyamido-triazole in androgen-independent prostate cancer. 1049


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