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

A variety of therapeutic strategies in oncology are focused on the inhibition of tumor-induced angiogenesis. Thus, there is a keen interest in methods which allow non-invasive monitoring of molecular targets involved in angiogenesis which would support information for planning and controlling corresponding therapies. Moreover, such techniques would provide an insight into the formation of new sprouting blood vessels, the involved processes and regulatory mechanisms in patients. At the moment, development of radiotracer based techniques is mainly concentrated on three different targets which include peptidic and non-peptidic alpha v beta 3-integrin binding antagonists, matrix metalloproteinase inhibitors and single chain anti-fibronectin antibody fragments. Development of radiolabeled MMP inhibitors is based on either the decapeptide Cys-Thr-Thr-His-Trp-Gly-Phe-Thr-Leu-Cys resulting from a phage display library or small molecular weight compounds. The in vitro data for these tracers are very promising. However, more detailed in vivo data are necessary to evaluate the potency of MMP-inhibitors for in-vivo imaging. The radiolabelled anti-ED-B single chain antibody fragment scFv L-19 shows selective accumulation in the tumor vasculature in a murine tumour model. In a first patient study a selective localisation of the (123)I-labeled tracer in lesions of different tumours was found. On the basis of the lead structure cyclo(-Arg-Gly-Asp-dPhe-Val) a variety of different radiolabeled RGD-peptides has been developed for the non-invasive determination of the alpha v beta 3 expression. These developments include peptides labeled with minimum structural alteration, peptide carbohydrate conjugates, peptidomimetics based on the RGD-structure as well as heterodimeric, homodimeric and homotetrameric ligand systems. Many of the tracers show high alpha v beta 3-affinity and selectivity in vitro and receptor selective tumour accumulation with high image contrast in different murine tumour models. Further studies have to demonstrate that this approach can be translated to clinical settings allowing visualisation of alpha v beta 3-positive tumours and alpha v beta 3 expression during tumour-induced angiogenesis in patients.
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PMID:Radiolabeled tracers for imaging of tumor angiogenesis and evaluation of anti-angiogenic therapies. 1513 68

Improvements in our understanding of the molecular basis of cancer have led to the clinical development of protein kinase inhibitors, which target pivotal molecules involved in intracellular signaling pathways implicated in tumorigenesis and progression. These novel targeted agents have demonstrated activity against a wide range of solid tumors, are generally better tolerated than standard chemotherapeutics, and may revolutionize the management of advanced refractory cancer. The ubiquitous Raf serine/threonine kinases are pivotal molecules within the Raf/mitogen extracellular kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway, which regulates cellular proliferation and survival. Raf kinase isoforms (wild-type Raf-1 or the b-raf V600E oncogene) are overactivated in a variety of solid tumor types, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), melanoma, and papillary thyroid carcinoma. In this review, the role of Raf in normal cells and in cancer is discussed, and an overview is given of Raf inhibitors currently in development, focusing on sorafenib tosylate (BAY 43-9006 or sorafenib). Sorafenib is the first oral multi-kinase inhibitor to be developed that targets Raf kinases (Raf-1, wild-type B-Raf, and b-raf V600E), in addition to receptor tyrosine kinases associated with angiogenesis (vascular endothelial growth factor receptor [VEGFR]-2/-3, platelet-derived growth factor receptor [PDGFR]-beta) or tumor progression (Flt-3, c-kit). Preclinical and clinical sorafenib data that led to its recent approval for the treatment of advanced RCC are summarized, along with current thinking on sorafenib's mechanism of effect on the tumor and tumor vasculature in melanoma and RCC.
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PMID:Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. 1689 Jul 95

Because angiogenic endothelial cells of the tumor vasculature represent an interesting target to potentiate the antivascular effect of photodynamic therapy, we recently described the conjugation of a photosensitizer [5-(4-carboxyphenyl)-10,15,20-triphenylchlorin (TPC)], via a spacer [6-aminohexanoic acid (Ahx)], to a vascular endothelial growth factor receptor-specific heptapeptide [H-Ala-Thr-Trp-Leu-Pro-Pro-Arg-OH (ATWLPPR)] and showed that TPC-Ahx-ATWLPPR binds to neuropilin-1. Because peptides often display low stability in biological fluids, we examined the in vivo and in vitro stability of this conjugate by high-performance liquid chromatography and matrix-assisted laser desorption ionization/time of flight mass spectrometry. TPC-Ahx-ATWLPPR was stable in vitro in human and mouse plasma for at least 24 h at 37 degrees C but, following i.v. injection in glioma-bearing nude mice, was degraded in vivo to various rates, depending on the organ considered. TPC-Ahx-A was identified as the main metabolic product, and biodistribution studies suggested that its appearance in plasma mainly resulted from the degradation of the peptidic moiety into organs of the reticuloendothelial system. According to in vitro cell culture experiments, TPC-Ahx-ATWLPPR was also significantly degraded after incorporation in human umbilical vein endothelial cells (HUVEC), mainly into TPC-Ahx-A and to a lesser extent into TPC-Ahx-AT and TPC-Ahx-ATWLPP. TPC-Ahx-ATWLPPR mostly localized into lysosomes, and when HUVEC were treated with the lysosomal enzymes' inhibitor ammonium chloride, this resulted in a significant decrease of the peptide degradation. This study provides essential information for the choice of the time of activation of the photosensitizer (drug-light interval) not to be exceeded and for the future design of more stable molecules.
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PMID:Metabolic profile of a peptide-conjugated chlorin-type photosensitizer targeting neuropilin-1: an in vivo and in vitro study. 1728 31

The vasculature within a tumor is highly disordered both structurally and functionally. Endothelial cells that comprise the vasculature are poorly connected causing vessel leakage and exposing the endothelium to a hypoxic microenvironment. Therefore, most anti-angiogenic therapies are generally inefficient and result in acquired resistance to increased hypoxia due to elimination of the vasculature. Recent studies have explored the efficacy of targeting metabolic pathways in tumor cells in combination with anti-angiogenic therapy. However, the metabolic alterations of endothelial cells in response to hypoxia have been relatively unexplored. Here, we measured polar metabolite levels in microvascular endothelial cells exposed to short- and long-term hypoxia with the goal of identifying metabolic vulnerabilities that can be targeted to normalize tumor vasculature and improve drug delivery. We found that many amino acid-related metabolites were altered by hypoxia exposure, especially within alanine-aspartate-glutamate, serine-threonine, and cysteine-methionine metabolism. Additionally, there were significant changes in de novo pyrimidine synthesis as well as glutathione and taurine metabolism. These results provide key insights into the metabolic alterations that occur in endothelial cells in response to hypoxia, which serve as a foundation for future studies to develop therapies that lead to vessel normalization and more efficient drug delivery.
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PMID:Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia. 3264 38