Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thromboembolism is one of the most common causes of death in cancer patients. Among the most frequent thrombotic complications in patients with cancer are disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and thrombocytosis. Clearly, these complications arise as tumor cells interact with almost all components of the hemostatic system including platelets. Platelets participate in tumor progression by contributing to the metastatic cascade, protecting tumor cells from immune surveillance, regulating tumor cell invasion, and angiogenesis. Platelets contain one of the largest stores of angiogenic and mitogenic factors and the tumor vasculature is leaky, which allows platelets to come in contact with the tumor and deposit multiple angiogenic factors including vascular endothelial growth factor (VEGF) and thrombin to tumor cells, which in turn contributes to tumor progression. This article reviews the recent literature on how platelets contribute to tumor growth, angiogenesis, and metastasis.
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PMID:Platelets and cancer: implications for antiangiogenic therapy. 1188 24

Anionic phospholipids are largely absent from the external leaflet of the plasma membrane of mammalian cells under normal conditions. Exposure of phosphatidylserine on the cell surface occurs during apoptosis, necrosis, cell injury, cell activation, and malignant transformation. In the present study, we determined whether anionic phospholipids become exposed on tumor vasculature. A monoclonal antibody, 9D2, which specifically recognizes anionic phospholipids, was injected into mice bearing a variety of orthotopic or ectopic tumors. Other mice received annexin V, a natural ligand that binds to anionic phospholipids. Both 9D2 and annexin V specifically localized to vascular endothelium in all of the tumors, and also to tumor cells in and around regions of necrosis. Between 15 and 40% of endothelial cells in tumor vessels were stained. No localization was detected on normal endothelium. Various factors and tumor-associated conditions known to be present in the tumor microenvironment were examined for their ability to cause exposure of anionic phospholipids in cultured endothelial cells, as judged by 9D2 and annexin V binding. Hypoxia/reoxygenation, acidity, thrombin, and inflammatory cytokines all induced exposure of anionic phospholipids. Hydrogen peroxide was also a strong inducer. Combined treatment with inflammatory cytokines and hypoxia/reoxygenation had greater than additive effects. Possibly, injury and activation of tumor endothelium by cytokines and reactive oxygen species induce exposure of anionic phospholipids, most likely phosphatidylserine. Anionic phospholipids on tumor vessels could potentially provide markers for tumor vessel targeting and imaging.
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PMID:Increased exposure of anionic phospholipids on the surface of tumor blood vessels. 1241 38

Angiogenesis is critical for several physiologic and pathophysiologic processes, and several angiogenesis inhibitors are now in clinical trials for the treatment of cancer. Antithrombin is a member of the serpin family of proteins and functions as an inhibitor of thrombin and other enzymes involved in the clotting cascade. While studying the inhibition of tumor growth by tumor mass in a human small cell lung cancer model, we discovered that the cleaved conformation of antithrombin has potent antiangiogenic and antitumor activity. The stable locked and latent forms of intact antithrombin, which are substantially similar in conformation to the cleaved form of the molecule, also inhibit angiogenesis and tumor growth in vivo and act selectively upon endothelial cells and the tumor vasculature. The intact native molecule does not have this effect. The discovery of antiangiogenic antithrombin provides further evidence that the clotting and fibrinolytic pathways are directly related to the regulation of angiogenesis. As for other endogenous angiogenesis inhibitors, the precise mechanism of action for antiangiogenic antithrombin has not been defined, but several studies now suggest that it may target the endothelial cell at multiple levels resulting in a profound blockade of the angiogenic cascade. In this paper, an overview of the angiogenesis inhibitor antiangiogenic antithrombin and a summary of the pertinent literature are provided.
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PMID:Antiangiogenic antithrombin. 1800 Jul 92

Oncolytic viruses (OVs) have been engineered or selected for cancer cell-specific infection however, we have found that following intravenous administration of vesicular stomatitis virus (VSV), tumor cell killing rapidly extends far beyond the initial sites of infection. We show here for the first time that VSV directly infects and destroys tumor vasculature in vivo but leaves normal vasculature intact. Three-dimensional (3D) reconstruction of infected tumors revealed that the majority of the tumor mass lacks significant blood flow in contrast to uninfected tumors, which exhibit relatively uniform perfusion. VSV replication in tumor neovasculature and spread within the tumor mass, initiates an inflammatory reaction including a neutrophil-dependent initiation of microclots within tumor blood vessels. Within 6 hours of intravenous administration of VSV and continuing for at least 24 hours, we observed the initiation of blood clots within the tumor vasculature whereas normal vasculature remained clot free. Blocking blood clot formation with thrombin inhibitors prevented tumor vascular collapse. Our results demonstrate that the therapeutic activity of an OV can go far beyond simple infection and lysis of malignant cells.
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PMID:Targeting tumor vasculature with an oncolytic virus. 2136 41

The past decades have witnessed the development of a field dedicated to targeting tumor vasculature for cancer therapy. In contrast to conventional chemotherapeutics that need to penetrate into tumor tissues for killing tumor cells, the agents targeting tumor vascular system have two major advantages: direct contact with vascular endothelial cells or the blood and less possibility to induce drug resistance because of high gene stability of endothelial cells. More specifically, various angiogenesis inhibitors (AIs) and vascular disrupting agents (VDAs) that block tumor blood supply to inhibit tumor progression, some of which have been applied clinically, have been described. However, off-target effects and high effective doses limit the utility of these formulations in cancer patients. Thus, new strategies with improved therapeutic efficacy and safety are needed for tumor vessel targeting therapy. With the burgeoning developments in nanotechnology, smart nanotherapeutics now offer unprecedented potential for targeting tumor vasculature. Based on specific structural and functional features of the tumor vasculature, a number of different nanoscale delivery systems have been proposed for cancer therapy. In this Account, we summarize several distinct strategies to modulate tumor vasculature with various smart nanotherapeutics for safe and effective tumor therapy developed by our research programs. Inspired by the blood coagulation cascade, we generated nanoparticle-mediated tumor vessel infarction strategies that selectively block tumor blood supply to starve the tumor to death. By specifically delivering thrombin loaded DNA nanorobots (Nanorobot-Th) into tumor vessels, an intratumoral thrombosis is triggered to induce vascular infarction and, ultimately, tumor necrosis. Mimicking the coagulation cascade, a smart polymeric nanogel achieves permanent and peripheral embolization of liver tumors. Considering the critical role of platelets in maintaining tumor vessel integrity, a hybrid (PLP-D-R) nanoparticle selectively depleting tumor-associated platelets (TAP) to boost tumor vessel permeability was developed for enhancing intratumoral drug accumulation. In addition, benefiting from a better understanding of the molecular and cellular underpinnings of vascular normalization, several tumor acidity responsive nanotherapeutics, encapsulating therapeutic peptides, and small interfering RNA were developed to correct the abnormal features of the tumor vasculature. This made the tumor vessels more efficient for drug delivery. While we are still exploring the mechanisms of action of these novel nanoformulations, we expect that the strategies summarized here will offer a promising platform to design effective next-generation nanotherapeutics against cancer and facilitate the clinical translation of smart nanotherapeutics that target tumor vasculature.
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PMID:Smart Nanotherapeutic Targeting of Tumor Vasculature. 3143 71