Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. However, clinical trials targeting the VEGF pathway are often ineffective, suggesting that other factors/pathways are also important in tumor angiogenesis. We have previously shown that the Notch ligand Delta-like 4 (DLL4) is up-regulated in tumor vasculature. Here, we show that DLL4, when expressed in tumor cells, functions as a negative regulator of tumor angiogenesis by reducing the number of blood vessels in all five types of xenografts, but acts as a positive driver for tumor growth in two of them (human glioblastoma and prostate cancer). The growth of in vivo models was not related to the effects on growth in vitro. DLL4 expressed in the tumor cells activated Notch signaling in host stromal/endothelial cells, increased blood vessel size, and improved vascular function within tumors. The promotion of tumor growth was, to some extent, due to a reduction of tumor hypoxia and apoptosis. DLL4-expressing tumor cells responded to anti-VEGF therapy with bevacizumab. A soluble form of DLL4 (D4ECD-Fc) blocked tumor growth in both bevacizumab-sensitive and bevacizumab-resistant tumors by disrupting vascular function despite increased tumor vessel density. In addition, we show that DLL4 is up-regulated in tumor cells and tumor endothelial cells of human glioblastoma. Our findings provide a rational basis for the development of novel antiangiogenic strategies via blockade of DLL4/Notch signaling and suggest that combined approaches for interrupting both DLL4 and VEGF pathways may improve antiangiogenic therapy.
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PMID:Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. 1805 50

Bevacizumab, a humanized monoclonal antibody used to treat recurrent and metastatic colorectal cancer, targets the vascular endothelial growth factor (VEGF) molecule. It is hypothesized that bevacizumab works by both depriving tumors of the neovascularity they require to grow, and by improving local delivery of chemotherapy through alterations of tumor vasculature permeability and Starling forces. Complications of bevacizumab treatment include bowel ischemia and perforation, but to date, these complications have only rarely been described as occurring at the site of presumably healed anastomoses following surgery. We report two cases of delayed, "spontaneous" low anterior colorectal anastomotic dehiscence and one right colon anastomotic colocutaneous fistula associated with bevacizumab therapy. After seeing three patients with complications arising from apparently healed low anterior colorectal or right colon anastomoses following initiation of bevacizumab therapy for treatment of metastatic colorectal cancer, we reviewed the experience of The Cancer Institute of New Jersey (CINJ) with use of bevacizumab in approximately 50 patients between April 2004 and December 2006. The three index cases had been treated surgically at CINJ but received chemotherapy elsewhere. None of the 50 patients receiving bevacizumab at CINJ who had previous colon or rectal anastomoses were identified as having this complication. The medical records of the three index cases were reviewed and analyzed. Additionally, a Medline search was performed to identify other reports documenting similar cases. Two reports of related cases were found in the literature. In two of our index cases who underwent low anterior anastomoses, the patients had received preoperative pelvic irradiation before their initial low anterior resection. In one of the two cases, the initial resection was complicated by an anastomotic leak requiring proximal diversion and then subsequent stoma takedown. In both cases, the dehiscence occurred more than 1 year after anastomosis, and became evident 1-10 months following initiation of bevacizumab treatment. In the third index case, a colocutaneous fistula arising from the anastomotic site presented 5 months following right colon resection and 3 months after starting adjuvant systemic therapy with FOLFOX (5-fluorouracil (5-FU), leucovorin, and oxaliplatin) and bevacizumab. Delayed colorectal anastomotic complications may occur in association with bevacizumab therapy. Contributing factors may include anastomotic leak at the time of the original operation and history of anastomotic irradiation. Clinicians treating patients who receive bevacizumab following colectomy for colorectal cancer should be aware of this possible life-threatening complication. These findings may also be relevant to the design of trials of the use of bevacizumab for the postoperative adjuvant treatment of patients with colorectal cancer.
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PMID:"Spontaneous," delayed colon and rectal anastomotic complications associated with bevacizumab therapy. 1809 68

There are clinical data showing encouraging results for combining chemoradiotherapy with interferon (IFN)-alpha (CapRI scheme) for the treatment of pancreatic carcinoma. Here, it was tried to evaluate the antiangiogenic effect of IFN-alpha in combination with chemotherapy. Mice were inoculated with syngeneic pancreatic carcinoma cells in the pancreas. After 5 days, the animals were treated with 5-fluorouracil (5-FU)+/-IFN-alpha. Tumor growth, vascular endothelial growth factor (VEGF) serum levels and VEGF-R expression, real-time reverse transcription-polymerase chain reaction of mRNA coding for RGS-5, an angiogenic pericyte marker at sites of physiologic and pathologic angiogenesis and impact of IFN-alpha treatment on vessel density by CD31 stain and intravital microscopy were analyzed. The addition of IFN-alpha to 5-FU-treatment decreased tumor volume, reduced serum level of VEGF, and down-regulated the expression of VEGF-receptor significantly. Furthermore, the combination therapy revealed a decrease in vessel density and a down-regulation of RGS-5, which is a protein involved in angiogenic tumor vasculature. IFN-alpha significantly improves the outcome of 5-FU-therapy in treating pancreatic carcinoma. This is at least partly mediated by IFN-alpha antiangiogenic properties, which acts along with 5-FU on the VEGF system, vessel density, and RGS-5 expression in pericytes.
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PMID:Interferon-alpha in combination with chemotherapy has potent antiangiogenic properties in an orthotopic mouse model for pancreatic adenocarcinoma. 1815 9

Among children with relapsed or refractory neuroblastoma, the prognosis is poor and novel therapeutic strategies are needed to improve long-term survival. As with other solid tumors, high vascular density within neuroblastoma is associated with advanced disease, and therapeutic regimens directed against the tumor vasculature may provide clinical benefit. The receptor tyrosine kinase RET is widely expressed in neuroblastoma and is known to activate key signal transduction pathways involved in tumor cell survival and progression including Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt. We investigated the effect of dual targeting of tumor cells and tumor endothelium with ZD6474, a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor 2, epidermal growth factor receptor, and RET. ZD6474 inhibited the phosphorylation of RET in neuroblastoma cells and had a direct effect on tumor cell viability in seven neuroblastoma cell lines. In a human neuroblastoma xenograft model, ZD6474 inhibited tumor growth by 85% compared with treatment with vehicle alone. In contrast, no significant inhibition of tumor growth was observed after treatment with bevacizumab, an antihuman VEGF monoclonal antibody, or the epidermal growth factor receptor inhibitor erlotinib, either alone or in combination. Immunohistochemical analysis showed that ZD6474 treatment led to an increase in endothelial cell apoptosis along with inhibition of VEGF receptor-2 activation on tumor endothelium. In conclusion, dual targeting of tumor cells, potentially through RET inhibition, and tumor vasculature with ZD6474 leads to potent antitumor effects. This approach merits further investigation for patients with neuroblastoma.
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PMID:Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium. 1824 71

Tissue factor (TF) is aberrantly expressed on tumor vascular endothelial cells (VECs) and on cancer cells in many malignant tumors, but not on normal VECs, making it a promising target for cancer therapy. As a transmembrane receptor for coagulation factor VIIa (fVIIa), TF forms a high-affinity complex with its cognate ligand, which is subsequently internalized through receptor-mediated endocytosis. Accordingly, we developed a method for selectively delivering EF24, a potent synthetic curcumin analog, to TF-expressing tumor vasculature and tumors using fVIIa as a drug carrier. EF24 was chemically conjugated to fVIIa through a tripeptide-chloromethyl ketone. After binding to TF-expressing targets by fVIIa, EF24 will be endocytosed along with the drug carrier and will exert its cytotoxicity. Our results showed that the conjugate inhibits vascular endothelial growth factor-induced angiogenesis in a rabbit cornea model and in a Matrigel model in athymic nude mice. The conjugate-induced apoptosis in tumor cells and significantly reduced tumor size in human breast cancer xenografts in athymic nude mice as compared with the unconjugated EF24. By conjugating potent drugs to fVIIa, this targeted drug delivery system has the potential to enhance therapeutic efficacy, while reducing toxic side effects. It may also prove to be useful for treating drug-resistant tumors and micro-metastases in addition to primary tumors.
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PMID:Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa. 1836 80

Oncolytic herpes simplex viruses (HSVs) possess direct oncolytic and antiangiogenic activities and are promising anticancer agents, but their efficacy, when used as single agents, leaves room for improvement. We investigated whether combination therapy of HSV with histone deacetylase inhibitor trichostatin A (TSA), an agent that also targets cancer cells and tumor vasculature, would result in enhanced efficacy. In vitro, TSA and G47Delta showed strong synergy of action against proliferating endothelial cells, varying degrees of synergistic action against most cancer cell lines, but no effect in quiescent, normal endothelial and prostate epithelial cells. Synergy is dependent on viral replication; however, it is not dependent on the dosing sequence of TSA and G47Delta, viral genetic alterations, infectivity, or replication kinetics of G47Delta. Using an isogenic cell system, we found that a high level of cellular cyclin D1 is also critically important for the interaction. Normal cells with low cyclin D1 levels were not subjected to toxicity by either agent. In tumor cells and proliferating endothelial cells, the combination treatment enhanced the inhibition of cyclin D1 and vascular endothelial growth factor (VEGF). Concurrent systemic TSA and intratumoral G47Delta administration resulted in enhanced antiangiogenesis and enhanced antitumoral efficacy in animal models. Therefore, combination treatment with TSA and oncolytic HSV provides a novel approach to cancer therapy.
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PMID:Trichostatin A and oncolytic HSV combination therapy shows enhanced antitumoral and antiangiogenic effects. 1838 12

Medulloblastoma is the most common malignant brain tumor of childhood. Surgery, radiation therapy, and chemotherapy successfully cure many patients, but survivors can suffer long-term toxicities affecting their neurocognitive and growth potential; furthermore, there is no curative therapy in up to 30% of cases, mainly because of our incomplete understanding of many of the underlying molecular and cellular processes. Angiogenesis is a hallmark of the progression of medulloblastoma and, over the last years, investigators have sought to develop effective and less toxic antiangiogenic strategies, including the inhibition or destruction of abnormal blood vessels using either antiangiogenic or vascular disrupting agents. However, the results are conflicting principally because of the complex biology of tumor vasculature and the irregular geometry of the vascular system in real space. In addition, current targets of antiangiogenic therapy, such as vascular endothelial growth factor (VEGF), are thought to be critical for both physiologic and pathologic angiogenesis, and clinical side effects of anti-VEGF therapy are beginning to emerge. We here review the state-of-the-art concerning antiangiogenic targets for medulloblastoma treatment, and discuss the complexity of the vascular system that intrinsically limits the efficacy of current strategies.
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PMID:Antiangiogenic strategies in medulloblastoma: reality or mystery. 1842 5

Molecular imaging is a key component of 21st-century cancer management. The vascular endothelial growth factor (VEGF)/VEGF receptor signaling pathway and integrin alpha v beta 3, a cell adhesion molecule, play pivotal roles in regulating tumor angiogenesis, the growth of new blood vessels. This review summarizes the current status of tumor angiogenesis imaging with SPECT, PET, molecular MRI, targeted ultrasound, and optical techniques. For integrin alpha v beta 3 imaging, only nanoparticle-based probes, which truly target the tumor vasculature rather than tumor cells because of poor extravasation, are discussed. Once improvements in the in vivo stability, tumor-targeting efficacy, and pharmacokinetics of tumor angiogenesis imaging probes are made, translation to clinical applications will be critical for the maximum benefit of these novel agents. The future of tumor angiogenesis imaging lies in multimodality and nanoparticle-based approaches, imaging of protein-protein interactions, and quantitative molecular imaging. Combinations of multiple modalities can yield complementary information and offer synergistic advantages over any modality alone. Nanoparticles, possessing multifunctionality and enormous flexibility, can allow for the integration of therapeutic components, targeting ligands, and multimodality imaging labels into one entity, termed "nanomedicine," for which the ideal target is tumor neovasculature. Quantitative imaging of tumor angiogenesis and protein-protein interactions that modulate angiogenesis will lead to more robust and effective monitoring of personalized molecular cancer therapy. Multidisciplinary approaches and cooperative efforts from many individuals, institutions, industries, and organizations are needed to quickly translate multimodality tumor angiogenesis imaging into multiple facets of cancer management. Not limited to cancer, these novel agents can also have broad applications for many other angiogenesis-related diseases.
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PMID:Multimodality molecular imaging of tumor angiogenesis. 1852 69

Multiple myeloma (MM) is an incurable plasma cell malignancy. The recent successes of the proteasome inhibitor bortezomib in MM therapy have prompted investigations of its efficacy in combination with other anticancer agents. Polyamines play important roles in regulating tumor cell proliferation and angiogenesis and represent an important therapeutic target. CGC-11093 is a novel polyamine analogue that has completed a phase I clinical trial for the treatment of cancer. Here, we report that CGC-11093 selectively augments the in vitro and in vivo antimyeloma activity of bortezomib. Specifically, the combination of CGC-11093 and bortezomib compromised MM viability and clonogenic survival, and increased drug-induced apoptosis over that achieved by either single agent. Xenografts of MM tumors treated with this combination had marked increases in phospho-c-Jun-NH(2)-kinase (JNK)-positive cells and apoptosis, and corresponding reductions in tumor burden, tumor vasculature, and the expression of proliferating cell nuclear antigen and the proangiogenic cytokine vascular endothelial growth factor. Furthermore, inhibition of JNK with a pharmacologic inhibitor or by selective knockdown blunted the efficacy of CGC-11093 and bortezomib. Therefore, CGC-11093 enhances the anticancer activity of bortezomib by augmenting JNK-mediated apoptosis and blocking angiogenesis. These findings support the study of the use of the combination of bortezomib and CGC-11093 in MM patients that fail to respond to frontline therapy.
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PMID:The novel polyamine analogue CGC-11093 enhances the antimyeloma activity of bortezomib. 1855 25

Gene targeting experiments have shown that Delta-like 4 (Dll4) is a vascular-specific Notch ligand critical to normal vascular development. Recent studies have demonstrated that inhibition of Dll4/Notch signaling in tumor-bearing mice resulted in excessive, yet nonproductive tumor neovascularization and unexpectedly reduced tumor growth. Because nonfunctional blood vessels have the potential to normalize, we explored the alternative approach of stimulating Notch signaling in the tumor vasculature to inhibit tumor growth. Here we show that retrovirus-induced over-expression of Dll4 in tumor cells activates Notch signaling in cocultured endothelial cells and limits vascular endothelial growth factor (VEGF)-induced endothelial cell growth. Tumors produced in mice by injection of human and murine tumor cells transduced with Dll4 were significantly smaller, less vascularized and more hypoxic than controls, and displayed evidence of Notch activation. In addition, tumor blood perfusion was reduced as documented by vascular imaging. These results demonstrate that Notch activation in the tumor microenvironment reduces tumor neovascularization and blood perfusion, and suggest that Dll4-induced Notch activation may represent an effective therapeutic approach for the treatment of solid tumors.
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PMID:Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth. 1857 11


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