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 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

Tumor angiogenesis is critical for the growth of primary cancers above 1-2 mm in diameter. A major vascular growth factor is VEGF, and approaches to inhibit VEGF have shown encouraging results in pre-clinical studies. The mechanisms involved in switching on angiogenesis involve activation of oncogenes and upregulation of the hypoxia-sensing pathway. These provide novel targets for therapy. Many anti-angiogenic drugs are in clinical trial currently and there are problems in assessing these types of drugs if they only cause disease stabilisation. It will be important to develop methods to assess inhibition of vascular growth in vivo. New generations of anti-angiogenesis drugs such as endostatin of angiostatin, which are more potent, may cause tumor regression, but this has not yet been studied in patients. These approaches for advanced disease should be more successful when applied early in an adjuvant situation. This will also require careful monitoring of long-term toxicity.
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PMID:Anti-angiogenesis therapy and strategies for integrating it with adjuvant therapy. 992 71

The "angiogenic switch" and tumor angiogenesis play a critical role in the growth and metastasis of solid tumors. Tumor angiogenesis is regulated by a balance of stimulators (e.g., VEGF, bFGF) and inhibitors of angiogenesis (e.g., angiostatin, endostatin, angiostatic steroids). Measuring angiogenesis (blood vessel density) and/or its main regulators such as VEGF and bFGF in solid tumors, or the levels of these growth factors in the serum or urine provides new and sensitive markers for tumor progression, metastasis and prognosis.
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PMID:The diagnostic and prognostic value of tumor angiogenesis. 1002 73

Tumors require ongoing angiogenesis to support their growth. Inhibition of angiogenesis by production of angiostatic factors should be a viable approach for cancer gene therapy. Endostatin, a potent angiostatic factor, was expressed in mouse muscle and secreted into the bloodstream for up to 2 weeks after a single intramuscular administration of the endostatin gene. The biological activity of the expressed endostatin was demonstrated by its ability to inhibit systemic angiogenesis. Moreover, the sustained production of endostatin by intramuscular gene therapy inhibited both the growth of primary tumors and the development of metastatic lesions. These results demonstrate the potential utility of intramuscular delivery of an antiangiogenic gene for treatment of disseminated cancers.
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PMID:Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene. 1020 81

The effect of photothermal vascular targeting, alone and in combination with antiangiogenic therapy, was evaluated using tumors produced in mice by transplantation of KB cells. Tumor growth inhibition and regression followed vascular damage produced by pulsed dye laser (PDL) radiation. Administration of the antiangiogenic agent all-trans-retinoic acid (RA) was associated with smaller average tumor volumes in the presence and absence of PDL irradiation, but this effect was not statistically significant. The ability of PDL photothermal vascular targeting to cause regression of tumors without harming normal tissue may be a consequence of preferential damage to supplying vessels at the tumor periphery.
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PMID:Tumor growth inhibition and regression induced by photothermal vascular targeting and angiogenesis inhibitor retinoic acid. 1037 92

The first time a nation made research a national priority was probably in 15th Century Portugal. While the Spanish built large galleons to ferry gold from the New World to Madrid, the Portuguese built small caravels to return with something more valuable: information. A National Navigational Institute was established in Sagres, where Prince Henry collated the raw data being delivered by the caravels: latitude, longitude, ocean depths, coastal landmarks, and current. Slowly, the caravels moved down the western coast of Africa, overcame the nautical and psychological obstacle of rounding the Horn, and slowly pushed up the Eastern coast. Each new voyage built on the incremental knowledge gleaned from the last and the certain knowledge of the ultimate goal. When Vasco DiGama reached India, the price of pepper in Venice plunged. A new route to the spice trade had been established, a route which did not require the payment of costly tributes at regular intervals along the land route, and a wealthy Empire which would last two centuries was established. The National Institutes of Health represent this nation's commitment to the importance of basic research. In the history of all mankind there has never been a greater, more consistent, and publically funded investment to understand the biology of human disease. Like the caravels, research laboratories and clinical trials have steadily moved forward with incremental progress toward a clearly visualized goal-the prevention and treatment of human disease. In the area of cancer research, we have clearly rounded the horn. The understanding of cancer at a basic level has now brought new targets for cancer treatment into sharper focus. We now understand cancer as a genetic disease. No longer do our therapies target a single cancer feature, uncontrolled growth. Instead, new vaccines like MART-1, gp100, p53 and ras peptides are targeting the cancer cell's ability to evade immune surveillance. Anti-angiogenesis agents like endostatin, Col-3, and angiostatin promise to inhibit the tumor's ability to make new blood vessels and convert cancer to a static, chronic disease. One advantage to these new angiogenesis inhibitors is their action against normal endothelial cells, rather than targeting the cancer itself. For this reason, the genetic plasticity of tumor cells, and their ability to develop drug resistance, is no longer relevant. The Clinton administration has recently announced its intention to add $4.7 billion to cancer research, essentially reaffirming the nation's initial investment of the National Cancer Act. The commitment could not have been better timed. When grants are funded at the 20th percentile, peer review does not work well. And when managed care makes clinical research nearly impossible, we erode the purpose of basic research and undermine the essence of our mission: the prevention and cure of human disease. The Administration's investment will prove to be wise. With the knowledge at hand, and the ability to translate this knowledge into new diagnostic, preventive and treatment approaches, we can begin to realistically vision cancer cures. A new era is at hand.
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PMID:Investment in Research as a National Priority. 1038 87

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

Gene therapy transfer of angiostatin and endostatin represents an alternative method of delivering angiogenic polypeptide inhibitors. We examined whether liposomes complexed to plasmids encoding angiostatin or endostatin inhibited angiogenesis and the growth of MDA-MB-435 tumors implanted in the mammary fat pads of nude mice. We determined that plasmids expressing angiostatin (PCI-Angio) or endostatin (PCI-Endo) effectively reduced angiogenesis using an in vivo Matrigel assay. We then investigated the efficacy of these plasmids in reducing the size of tumors implanted in the mammary fat pad of nude mice. Both PCI-Angio and PCI-Endo significantly reduced tumor size when injected intratumorally (P < 0.05). Compared to the untreated control group, the mice treated with PCI-Angio and PCI-Endo exhibited a reduction in tumor size of 36% and 49%, respectively. In addition, we found that i.v. injections of liposomes complexed to PCI-Endo reduced tumor growth in the nude mice by nearly 40% when compared to either empty vector (PCI) or untreated controls (P < 0.05). These findings provide a basis for the further development of nonviral delivery of antiangiogenic genes.
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PMID:Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice. 1072 14

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, a C-terminal product of collagen XVIII, is a very powerful angiogenesis inhibitor. In vivo experiments in mice indicate that endostatin dramatically reduces tumor mass without causing the onset of any resistance to the treatment. Recently, a 12-aa shorter human endostatin has been purified from plasma, but is ineffective in in vitro angiogenesis assays. Here we report that the full-length human recombinant endostatin has a potent inhibitory activity in in vitro angiogenesis assays. Two powerful angiogenic factors were used to stimulate endothelial cells: FGF-2 and VEGF-165. Endostatin prevented cell growth both in the basal condition and after stimulation with FGF-2 or VEGF-165. Migration of microvascular endothelial cells toward FGF-2 or VEGF-165 was impaired, both when cells were pretreated with the inhibitor and when endostatin was added together with the growth factors. Furthermore, experiments of inhibition of proliferation performed on nonmicroendothelial cells showed that endostatin was ineffective. This study indicates that human endostatin is a potent angiogenesis inhibitor and suggests its use in human anticancer therapy.
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PMID:Inhibitory effect of full-length human endostatin on in vitro angiogenesis. 1049 Dec 94


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