BibSonomyburst/user/kanefendt/antagonistsBibSonomy RSS feed for /user/kanefendt/antagonists2012-02-16T23:23:21+01:00http://www.bibsonomy.org/bibtex/2f4e6a5de4f2b9e413dbb8109656c7786/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; A Aged Agents Antineoplastic Endothelial Factor Female Growth Humans Hypertension Indoles Middle Neurotoxicity Purpura Pyrroles Receptor-2 Syndromes Thrombocytopenic Thrombotic Vascular adverse antagonists chemically effects etiology induced inhibitors <span class="authorEditorList"><a href="/author/Kapiteijn">E. Kapiteijn</a>, <a href="/author/Brand">A. Brand</a>, <a href="/author/Kroep">J. Kroep</a>, and <a href="/author/Gelderblom">H. Gelderblom</a> </span><em>Ann.Oncol.</em> <em>18(10):1745-1747</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Ann.Oncol.101745-1747Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome182007& A Aged Agents Antineoplastic Endothelial Factor Female Growth Humans Hypertension Indoles Middle Neurotoxicity Purpura Pyrroles Receptor-2 Syndromes Thrombocytopenic Thrombotic Vascular adverse antagonists chemically effects etiology induced inhibitors http://www.bibsonomy.org/bibtex/2143cacfb64ea0a7986d0ab5e71479dba/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Angiogenesis Animals Blood Endothelial Factors Growth Humans Inhibitors Laboratories Neoplasms Neovascularization Pathologic Research Vascular Vessels antagonists blood cells drug inhibitors pathology supply therapeutic therapy use <span class="authorEditorList"><a href="/author/Fukumura">D. Fukumura</a>, and <a href="/author/Jain">R. K. Jain</a> </span><em>Microvasc.Res.</em> <em>74(2-3):72-84</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Microvasc.Res.2-372-84Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization742007& Angiogenesis Animals Blood Endothelial Factors Growth Humans Inhibitors Laboratories Neoplasms Neovascularization Pathologic Research Vascular Vessels antagonists blood cells drug inhibitors pathology supply therapeutic therapy use A solid tumor forms an organ-like entity comprised of neoplastic cells and non-transformed host stromal cells embedded in an extracellular matrix. Similar to normal tissues, blood vessels nourish cells residing in tumors. However, unlike normal blood vessels, tumor vasculature has abnormal organization, structure, and function. Tumor vessels are leaky and blood flow is heterogeneous and often compromised. Vascular hyperpermeability and the lack of functional lymphatic vessels inside tumors cause elevation of interstitial fluid pressure in solid tumors. Each of these abnormalities forms a physiological barrier to the delivery of therapeutic agents to tumors. Furthermore, elevated tumor interstitial fluid pressure increases fluid flow from the tumor margin into the peri-tumor area and may facilitate peri-tumor lymphatic hyperplasia and metastasis. Abnormal microcirculation in tumors also leads to a hostile microenvironment characterized by hypoxia and acidosis, which hinder the effectivehttp://www.bibsonomy.org/bibtex/2fe9b6da17080b89b77fd623f65128cf0/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Adhesion Albuminuria Angiotensin Animals Atherosclerosis B Blood C57BL Cardiovascular Cell Cells Chain Chloride Cultured Dietary Diseases Endothelial Ester Expression Factor-alpha Fusion Gene Humans Hypertension I-kappa II III Inbred Inflammation Intercellular Kidney Methyl Mice Models Molecule-1 NF-kappa NG-Nitroarginine Necrosis Nephritis Nitric Organ Oxide Polymerase Pressure Proteins Reaction Receptor Recombinant Regulation Research Reverse Signal Sodium Specificity Synthase TIE-1 Transcriptase Transduction Transgenic Tumor Type Vascular antagonists biosynthesis blood cells complications control etiology genetics inhibitors metabolism physiology physiopathology prevention protein toxicity <span class="authorEditorList"><a href="/author/Henke">N. Henke</a>, <a href="/author/Schmidt-Ullrich">R. Schmidt-Ullrich</a>, <a href="/author/Dechend">R. Dechend</a>, <a href="/author/Park">J. K. Park</a>, <a href="/author/Qadri">F. Qadri</a>, <a href="/author/Wellner">M. Wellner</a>, <a href="/author/Obst">M. Obst</a>, <a href="/author/Gross">V. Gross</a>, <a href="/author/Dietz">R. Dietz</a>, <a href="/author/Luft">F. C. Luft</a>, <a href="/author/Scheidereit">C. Scheidereit</a>, and <a href="/author/Muller">D. N. Muller</a> </span><em>Circ.Res.</em> <em>101(3):268-276</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Circ.Res.3268-276Vascular endothelial cell-specific NF-kappaB suppression attenuates hypertension-induced renal damage1012007& Adhesion Albuminuria Angiotensin Animals Atherosclerosis B Blood C57BL Cardiovascular Cell Cells Chain Chloride Cultured Dietary Diseases Endothelial Ester Expression Factor-alpha Fusion Gene Humans Hypertension I-kappa II III Inbred Inflammation Intercellular Kidney Methyl Mice Models Molecule-1 NF-kappa NG-Nitroarginine Necrosis Nephritis Nitric Organ Oxide Polymerase Pressure Proteins Reaction Receptor Recombinant Regulation Research Reverse Signal Sodium Specificity Synthase TIE-1 Transcriptase Transduction Transgenic Tumor Type Vascular antagonists biosynthesis blood cells complications control etiology genetics inhibitors metabolism physiology physiopathology prevention protein toxicity Nuclear factor kappa B (NF-kappaB) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell-specific NF-kappaB suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell-restricted NF-kappaB super-repressor IkappaBalphaDeltaN (Tie-1-DeltaN mice) overexpression. We confirmed cell-specific IkappaBalphaDeltaN expression and reduced NF-kappaB activity after TNF-alpha stimulation in primary endothelial cell culture. To induce hypertension with target-organ damage, we fed mice a high-salt diet and N(omega)-nitro-l-arginine-methyl-ester (L-NAME) and infused angiotensin (Ang) II. This treatment caused a 40-mm Hg blood pressure increase in both Tie-1-DeltaN and control mice. In contrast to control mice, Tie-1-DeltaN mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-kappaB targets VCAM-1 and ICAM-1, compared with contrhttp://www.bibsonomy.org/bibtex/21d3ba1cc74ddebe211f5e063d1db007f/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Animals Antibodies Antitumor Assays BALB Binding C Cell D Endothelial Factor Growth Human Humans Immunohistochemistry Inbred Ligands Mice Model Monoclonal Neoplasms Neovascularization Nude Pathologic Processes Receptor-3 Research Vascular Xenograft analysis antagonists blood immunology inhibitors metabolism pharmacology supply therapy <span class="authorEditorList"><a href="/author/Laakkonen">P. Laakkonen</a>, <a href="/author/Waltari">M. Waltari</a>, <a href="/author/Holopainen">T. Holopainen</a>, <a href="/author/Takahashi">T. Takahashi</a>, <a href="/author/Pytowski">B. Pytowski</a>, <a href="/author/Steiner">P. Steiner</a>, <a href="/author/Hicklin">D. Hicklin</a>, <a href="/author/Persaud">K. Persaud</a>, <a href="/author/Tonra">J. R. Tonra</a>, <a href="/author/Witte">L. Witte</a>, and <a href="/author/Alitalo">K. Alitalo</a> </span><em>Cancer Res.</em> <em>67(2):593-599</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Cancer Res.2593-599Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth672007& Animals Antibodies Antitumor Assays BALB Binding C Cell D Endothelial Factor Growth Human Humans Immunohistochemistry Inbred Ligands Mice Model Monoclonal Neoplasms Neovascularization Nude Pathologic Processes Receptor-3 Research Vascular Xenograft analysis antagonists blood immunology inhibitors metabolism pharmacology supply therapy Vascular endothelial growth factor receptor 3 (VEGFR-3) binds VEGF-C and VEGF-D and is essential for the development of the lymphatic vasculature. Experimental tumors that overexpress VEGFR-3 ligands induce lymphatic vessel sprouting and enlargement and show enhanced metastasis to regional lymph nodes and beyond, whereas a soluble form of VEGFR-3 that blocks receptor signaling inhibits these changes and metastasis. Because VEGFR-3 is also essential for the early blood vessel development in embryos and is up-regulated in tumor angiogenesis, we wanted to determine if an antibody targeting the receptor that interferes with VEGFR-3 ligand binding can inhibit primary tumor growth. Our results show that antibody interference with VEGFR-3 function can inhibit the growth of several human tumor xenografts in immunocompromised mice. Immunohistochemical analysis showed that the blood vessel density of anti-VEGFR-3-treated tumors was significantly decreased and hypoxic and necrotic tumor tissue wahttp://www.bibsonomy.org/bibtex/2506ad4630500172729537a9ce24caf9c/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Aged Agents Animals Antineoplastic Arteries Artery Blood Carcinoma Coronary Disease Failure Female Gastrointestinal Heart Humans Hypertension Indoles Kinase Kinases Male Mice Middle Multicenter Pressure Protein-Tyrosine Pyrroles Rats Research Retrospective Safety Stroke Stromal Studies Topic Tumors Tyrosine Volume adverse antagonists as blood chemically drug effects induced inhibitors methods therapeutic therapy toxicity use <span class="authorEditorList"><a href="/author/Chu">T. F. Chu</a>, <a href="/author/Rupnick">M. A. Rupnick</a>, <a href="/author/Kerkela">R. Kerkela</a>, <a href="/author/Dallabrida">S. M. Dallabrida</a>, <a href="/author/Zurakowski">D. Zurakowski</a>, <a href="/author/Nguyen">L. Nguyen</a>, <a href="/author/Woulfe">K. Woulfe</a>, <a href="/author/Pravda">E. Pravda</a>, <a href="/author/Cassiola">F. Cassiola</a>, <a href="/author/Desai">J. Desai</a>, <a href="/author/George">S. George</a>, <a href="/author/Morgan">J. A. Morgan</a>, <a href="/author/Harris">D. M. Harris</a>, <a href="/author/Ismail">N. S. Ismail</a>, <a href="/author/Chen">J. H. Chen</a>, <a href="/author/Schoen">F. J. Schoen</a>, <a href="/author/van den Abbeele">A. D. van den Abbeele</a>, <a href="/author/Demetri">G. D. Demetri</a>, <a href="/author/Force">T. Force</a>, and <a href="/author/Chen">M. H. Chen</a> </span><em>Lancet</em> <em>370(9604):2011-2019</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Lancet96042011-2019Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib3702007& Aged Agents Animals Antineoplastic Arteries Artery Blood Carcinoma Coronary Disease Failure Female Gastrointestinal Heart Humans Hypertension Indoles Kinase Kinases Male Mice Middle Multicenter Pressure Protein-Tyrosine Pyrroles Rats Research Retrospective Safety Stroke Stromal Studies Topic Tumors Tyrosine Volume adverse antagonists as blood chemically drug effects induced inhibitors methods therapeutic therapy toxicity use BACKGROUND: Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours. METHODS: We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardihttp://www.bibsonomy.org/bibtex/277bee5565bfa32594d200c2c9fedca93/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Antibodies Biological Carcinoma Dosage Drug Epidermal Factor Gene Growth Human Humans Immunohistochemistry Inhibitors Kinase Kinases Lung Markers Monoclonal Mutation Neoplasm Neoplasms Non-Small-Cell Phosphoproteins Predictive Protein Protein-Tyrosine Proteins Proto-Oncogene Quinazolines Receptor Resistance Tests Tyrosine Value analysis antagonists c-akt drug effects erbB-2 erbB-3 genetics identify inhibitors of protein response therapeutic therapy use <span class="authorEditorList"><a href="/author/Cappuzzo">F. Cappuzzo</a>, <a href="/author/Toschi">L. Toschi</a>, <a href="/author/Finocchiaro">G. Finocchiaro</a>, <a href="/author/Ligorio">C. Ligorio</a>, and <a href="/author/Santoro">A. Santoro</a> </span><em>Int.J.Biol.Markers</em> <em>22(1 Suppl 4):S10-S23</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Int.J.Biol.Markers1 Suppl 4S10-S23Surrogate predictive biomarkers for response to anti-EGFR agents: state of the art and challenges222007& Antibodies Biological Carcinoma Dosage Drug Epidermal Factor Gene Growth Human Humans Immunohistochemistry Inhibitors Kinase Kinases Lung Markers Monoclonal Mutation Neoplasm Neoplasms Non-Small-Cell Phosphoproteins Predictive Protein Protein-Tyrosine Proteins Proto-Oncogene Quinazolines Receptor Resistance Tests Tyrosine Value analysis antagonists c-akt drug effects erbB-2 erbB-3 genetics identify inhibitors of protein response therapeutic therapy use The epidermal growth factor receptor (EGFR) plays a key role in cancer development and progression in several human malignancies including non-small cell lung cancer (NSCLC). Several strategies aimed at inhibiting the EGFR have been investigated in the last years, including the use of small tyrosine kinase inhibitors (TKIs) directed against the intracellular domain of the receptor and monoclonal antibodies targeting its extracellular portion. Subgroups of patients who are more likely to respond to TKIs have been identified based on both clinical and biological features. Never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, while presence of drug-sensitive EGFR mutations and EGFR gene gain represent critical biological variables associated with an improved outcome for patients exposed to these agents. Recent studies have highlighted the existence of biological factors involved in intrinsic and acquired resistance to TKIs,http://www.bibsonomy.org/bibtex/2beabba54bd2d560c3e6e69f70f2777bd/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Aged Agents Angiogenesis Antineoplastic Carcinoma Cardiomyopathies Cell Dysfunction Echocardiography Female Humans Illness Index Indoles Inhibitors Kidney Kinase Kinases Left Neoplasms Protein-Tyrosine Pyrroles Renal Severity Tyrosine Ventricular adverse antagonists chemically contraindications drug effects induced inhibitors of therapy <span class="authorEditorList"><a href="/author/Chorianopoulos">E. Chorianopoulos</a>, <a href="/author/Jager">D. Jager</a>, <a href="/author/Katus">H. A. Katus</a>, and <a href="/author/Frey">N. Frey</a> </span><em>Clin.Res.Cardiol.</em> <em>96(11):829-830</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Clin.Res.Cardiol.11829-830Severe cardiomyopathy in a patient with renal cell carcinoma after treatment with the novel tyrosine kinase inhibitor sunitinib962007& Aged Agents Angiogenesis Antineoplastic Carcinoma Cardiomyopathies Cell Dysfunction Echocardiography Female Humans Illness Index Indoles Inhibitors Kidney Kinase Kinases Left Neoplasms Protein-Tyrosine Pyrroles Renal Severity Tyrosine Ventricular adverse antagonists chemically contraindications drug effects induced inhibitors of therapy http://www.bibsonomy.org/bibtex/2602435fc1730c5168f565863b795701d/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Adaptor Antibodies Benzenesulfonates Biological Delivery Diseases Drug Enzyme Heart Human Humans Indoles Inhibitors Kinase Kinases Models Monoclonal Mutation Neoplasms Protein Protein-Tyrosine Proteins Proto-Oncogene Pyridines Pyrroles Quinazolines Research Signal Systems Transducing Tyrosine adverse antagonists c-abl cells chemically development drug effects growth induced inhibitors physiology protein response therapy toxicity <span class="authorEditorList"><a href="/author/Force">T. Force</a>, <a href="/author/Krause">D. S. Krause</a>, and <a href="/author/van Etten">R. A. van Etten</a> </span><em>Nat.Rev.Cancer</em> <em>7(5):332-344</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Nat.Rev.Cancer5332-344Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition72007& Adaptor Antibodies Benzenesulfonates Biological Delivery Diseases Drug Enzyme Heart Human Humans Indoles Inhibitors Kinase Kinases Models Monoclonal Mutation Neoplasms Protein Protein-Tyrosine Proteins Proto-Oncogene Pyridines Pyrroles Quinazolines Research Signal Systems Transducing Tyrosine adverse antagonists c-abl cells chemically development drug effects growth induced inhibitors physiology protein response therapy toxicity Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of "targeted therapies", particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been associated with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cellshttp://www.bibsonomy.org/bibtex/253e1171b8a15a9f6bacf8979fae3a8bb/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; A Angiogenesis Animals Carcinoma Clinical Design Drug Endothelial Factor France Growth Humans Indoles Inhibitors Kinase Kinases Neoplasm Neoplasms Protein-Tyrosine Pyrroles Receptors Resistance Topic Trials Tyrosine Vascular adverse antagonists as biosynthesis blood drug effects enzymology inhibitors metabolism pharmacology response supply therapeutic therapy use <span class="authorEditorList"><a href="/author/Faivre">S. Faivre</a>, <a href="/author/Demetri">G. Demetri</a>, <a href="/author/Sargent">W. Sargent</a>, and <a href="/author/Raymond">E. Raymond</a> </span><em>Nat.Rev.Drug Discov.</em> <em>6(9):734-745</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Nat.Rev.Drug Discov.9734-745Molecular basis for sunitinib efficacy and future clinical development62007& A Angiogenesis Animals Carcinoma Clinical Design Drug Endothelial Factor France Growth Humans Indoles Inhibitors Kinase Kinases Neoplasm Neoplasms Protein-Tyrosine Pyrroles Receptors Resistance Topic Trials Tyrosine Vascular adverse antagonists as biosynthesis blood drug effects enzymology inhibitors metabolism pharmacology response supply therapeutic therapy use Sunitinib malate (SU11248/Sutent; Pfizer) is a multitargeted tyrosine kinase inhibitor that has potent anti-angiogenic and antitumour activities. Definitive efficacy has been demonstrated in advanced renal cell carcinoma and in gastrointestinal stromal tumours that are refractory or intolerant to imatinib (Gleevec; Novartis), which has provided the basis for the recent regulatory approvals for these indications. This article summarizes the discovery and development of sunitinib, and discusses key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance, and their significance for the future development of sunitinib and other multikinase inhibitorshttp://www.bibsonomy.org/bibtex/2369c88f24f6cf696fc67db33cc272b4f/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; A Angiogenesis Antibodies Endothelial Factor Growth Humans Inhibitors Kinase Kinases Medical Monoclonal Neoplasms Neovascularization Oncology Pathologic Protein Protein-Tyrosine Receptors Tyrosine Vascular adverse antagonists blood control drug effects inhibitors prevention protein supply therapy toxicity <span class="authorEditorList"><a href="/author/Eskens">F. A. Eskens</a>, and <a href="/author/Verweij">J. Verweij</a> </span><em>Eur.J.Cancer</em> <em>42(18):3127-3139</em> (<em>2006</em>)Fri Feb 05 11:28:39 CET 2010Eur.J.Cancer183127-3139The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review422006& A Angiogenesis Antibodies Endothelial Factor Growth Humans Inhibitors Kinase Kinases Medical Monoclonal Neoplasms Neovascularization Oncology Pathologic Protein Protein-Tyrosine Receptors Tyrosine Vascular adverse antagonists blood control drug effects inhibitors prevention protein supply therapy toxicity Clinical experience with vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors is rapidly increasing, and some compounds have already been approved for regular anticancer treatment. Apart from their activity, much attention has been focussed on the clinical toxicity profile of these compounds. This review describes the most frequently occurring side-effects of both antibodies and tyrosine kinase inhibitors and discusses some of the underlying mechanisms. Some practical guidelines for treatment of the side-effects are givenhttp://www.bibsonomy.org/bibtex/2a983fe521c531b49f0265112de4eeb86/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; A Angiogenesis Clinical Endothelial Factor Growth Human Humans Inhibitors Kinase Kinases Lung Neoplasms Piperidines Protein Protein-Tyrosine Proteins Quinazolines Receptors Research Safety Topic Trials Tyrosine Vascular antagonists as drug inhibitors metabolism protein therapeutic therapy use <span class="authorEditorList"><a href="/author/Morabito">A. Morabito</a>, <a href="/author/De">Maio E. De</a>, <a href="/author/Di">Maio M. Di</a>, <a href="/author/Normanno">N. Normanno</a>, and <a href="/author/Perrone">F. Perrone</a> </span><em>Oncologist.</em> <em>11(7):753-764</em> (<em>2006</em>)Fri Feb 05 11:28:39 CET 2010Oncologist.7753-764Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions112006& A Angiogenesis Clinical Endothelial Factor Growth Human Humans Inhibitors Kinase Kinases Lung Neoplasms Piperidines Protein Protein-Tyrosine Proteins Quinazolines Receptors Research Safety Topic Trials Tyrosine Vascular antagonists as drug inhibitors metabolism protein therapeutic therapy use Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of peptide growth factors and receptors are key regulators of this process. Agents directed either against VEGF or VEGF receptors (VEGFRs) have been developed. The tyrosine kinase inhibitors of VEGFRs are low-molecular-weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEG-FRs, resulting in blockade of intracellular signaling. Several of these agents are currently in different phases of clinical development. Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies, respectively. Positive results also have been reported with the combination of ZD6474 and chemotherapy in previously treated non-small cell lung cancer patients. For othhttp://www.bibsonomy.org/bibtex/2463d0b247e477cd3460c6d76976388b8/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; A Administration Agents Angiogenesis Antineoplastic Biological Blood Clinical Coagulation Drug Endothelial Factor Function Growth Humans Hypertension Inhibitors Left Models Neoplasm Platelets Research Resistance Schedule Signal Thrombosis Topic Transduction Trials Vascular Ventricular administration adverse antagonists as chemically dosage drug effects etiology induced inhibitors physiology toxicity <span class="authorEditorList"><a href="/author/Verheul">H. M. Verheul</a>, and <a href="/author/Pinedo">H. M. Pinedo</a> </span><em>Nat.Rev.Cancer</em> <em>7(6):475-485</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Nat.Rev.Cancer6475-485Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition72007& A Administration Agents Angiogenesis Antineoplastic Biological Blood Clinical Coagulation Drug Endothelial Factor Function Growth Humans Hypertension Inhibitors Left Models Neoplasm Platelets Research Resistance Schedule Signal Thrombosis Topic Transduction Trials Vascular Ventricular administration adverse antagonists as chemically dosage drug effects etiology induced inhibitors physiology toxicity Contrary to initial expectations, angiogenesis inhibitors can cause toxicities in patients with cancer. The toxicity profiles of these inhibitors reflect the disturbance of growth factor signalling pathways that are important for maintaining homeostasis. Experiences with angiogenesis inhibitors in clinical trials indicate that short-term toxicities are mostly manageable. However, these agents will also be given in prolonged treatment strategies, so we need to anticipate possible long-term toxicities. In addition, understanding the molecular mechanisms involved in the toxicity of angiogenesis inhibition should allow more specific and more potent inhibitors to be developedhttp://www.bibsonomy.org/bibtex/223511f1ba021049533daca96017b211a/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; A Adult Aged Antibodies Antineoplastic Biological Camptothecin Chemotherapy Colorectal Combined Disease Endothelial Factor Female Growth Humans Male Markers Medical Middle Monoclonal Neoplasms Oncology Outcome Progression Prospective Protocols Rate Studies Survival Treatment Tumor Vascular administration analogs antagonists blood derivatives dosage drug inhibitors methods mortality response therapeutic therapy trends use <span class="authorEditorList"><a href="/author/Vincenzi">B. Vincenzi</a>, <a href="/author/Santini">D. Santini</a>, <a href="/author/Russo">A. Russo</a>, <a href="/author/Gavasci">M. Gavasci</a>, <a href="/author/Battistoni">F. Battistoni</a>, <a href="/author/Dicuonzo">G. Dicuonzo</a>, <a href="/author/Rocci">L. Rocci</a>, <a href="/author/Rosaria">V. M. Rosaria</a>, <a href="/author/Gebbia">N. Gebbia</a>, and <a href="/author/Tonini">G. Tonini</a> </span><em>Pharmacogenomics.</em> <em>8(4):319-327</em> (<em>2007</em>)Fri Feb 05 11:28:39 CET 2010Pharmacogenomics.4319-327Circulating VEGF reduction, response and outcome in advanced colorectal cancer patients treated with cetuximab plus irinotecan82007& A Adult Aged Antibodies Antineoplastic Biological Camptothecin Chemotherapy Colorectal Combined Disease Endothelial Factor Female Growth Humans Male Markers Medical Middle Monoclonal Neoplasms Oncology Outcome Progression Prospective Protocols Rate Studies Survival Treatment Tumor Vascular administration analogs antagonists blood derivatives dosage drug inhibitors methods mortality response therapeutic therapy trends use OBJECTIVE: We designed this trial to investigate if modifications in levels of circulating vascular endothelial growth factor (VEGF) may be related to clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. METHODS: A total of 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab plus weekly irinotecan. VEGF circulating levels were assessed at the following time points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. RESULTS: Basal VEGF median levels were significantly decreased just 1 day after the first anticancer infusion (p = 0.016) and reached the highest statistical significance 92 days after the first infusion (p < 0.0001). A total of 22 patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusionhttp://www.bibsonomy.org/bibtex/2ee1fa6cc385bc0da43b7dc0595066e27/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Adult Aged Animals C Data Doxycycline Elephantiasis Endothelial Factor Female Filarial Filaricides Growth Humans Hydrocele Intercellular Lymphatic Lymphedema Male Microfilaria Middle Molecular Outcome Parasitemia Peptides Plasma Proteins Receptor-3 Research Sequence Signaling System Testicular Testis Treatment Vascular Vessels Wolbachia and antagonists blood drug effects immunology inhibitors isolation parasitology pathology physiology protein purification therapeutic therapy ultrasonography use <span class="authorEditorList"><a href="/author/Debrah">A. Y. Debrah</a>, <a href="/author/Mand">S. Mand</a>, <a href="/author/Specht">S. Specht</a>, <a href="/author/Marfo-Debrekyei">Y. Marfo-Debrekyei</a>, <a href="/author/Batsa">L. Batsa</a>, <a href="/author/Pfarr">K. Pfarr</a>, <a href="/author/Larbi">J. Larbi</a>, <a href="/author/Lawson">B. Lawson</a>, <a href="/author/Taylor">M. Taylor</a>, <a href="/author/Adjei">O. Adjei</a>, and <a href="/author/Hoerauf">A. Hoerauf</a> </span><em>PLoS.Pathog.</em> <em>2(9):e92</em> (<em>2006</em>)Fri Feb 05 11:28:39 CET 2010PLoS.Pathog.9e92Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis22006& Adult Aged Animals C Data Doxycycline Elephantiasis Endothelial Factor Female Filarial Filaricides Growth Humans Hydrocele Intercellular Lymphatic Lymphedema Male Microfilaria Middle Molecular Outcome Parasitemia Peptides Plasma Proteins Receptor-3 Research Sequence Signaling System Testicular Testis Treatment Vascular Vessels Wolbachia and antagonists blood drug effects immunology inhibitors isolation parasitology pathology physiology protein purification therapeutic therapy ultrasonography use Lymphatic filariasis is a disease of considerable socioeconomic burden in the tropics. Presently used antifilarial drugs are able to strongly reduce transmission and will thus ultimately lower the burden of morbidity associated with the infection, however, a chemotherapeutic principle that directly induces a halt or improvement in the progression of the morbidity in already infected individuals would constitute a major lead. In search of such a more-effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 33 microfilaremic and 18 lymphedema patients took part in a double-blind, placebo-controlled trial of a 6-wk regimen of 200 mg/day doxycycline. Four months after doxycycline treatment, all patients received 150-200 microg/kg ivermectin and 400 mg albendazole. Patients were monitored for Wolbachia and microfilaria loads, antigenemia, filarial dance sign (FDS), dilation of supratesticular lymphatic vessels, and plasma levels of lymphangiogehttp://www.bibsonomy.org/bibtex/22241f0587b827c94106b86f8ce995a2c/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Animals Antibodies Biomarkers Carcinoma Colorectal Drug Epidermal Europe Factor Factors Growth Humans Immunologic Ligands Medical Monoclonal Mutation Neoplasm Neoplasms Oncology Pharmacological Phosphorylation Prognosis Receptor Resistance Tyrosine antagonists genetics inhibitors pharmacology response therapeutic therapy use <span class="authorEditorList"><a href="/author/Carcereny">E. Carcereny</a>, and <a href="/author/Maurel">J. Maurel</a> </span><em>Rev.Recent Clin.Trials</em> <em>1(2):113-118</em> (<em>2006</em>)Fri Feb 05 11:28:39 CET 2010Rev.Recent Clin.Trials2113-118Monoclonal antibodies against epidermal growth factor receptor in advanced colorectal carcinoma: clinical efficacy and markers of sensitivity12006& Animals Antibodies Biomarkers Carcinoma Colorectal Drug Epidermal Europe Factor Factors Growth Humans Immunologic Ligands Medical Monoclonal Mutation Neoplasm Neoplasms Oncology Pharmacological Phosphorylation Prognosis Receptor Resistance Tyrosine antagonists genetics inhibitors pharmacology response therapeutic therapy use Colorectal cancer (CRC) is the second most common cancer in Western Europe. Combinations of oxaliplatin or irinotecan with fluorouracil have increased responses in first-line therapy up to 40%, but prognosis is still poor. Almost 80% of patients will progress during the first year of treatment and usually become refractory to all current therapies, including EGFR inhibitors. The likelihood of achieving a response to cetuximab-based therapy is not related to overt levels of epidermal growth factor receptor (EGFR) expression in the tumor. Whilst other markers of cetuximab activity, such as phosphorylation status of the EGFR, quantification of ligands and polymorphisms in the promoter or in first intronic region, have not been validated, response rate correlates with the intensity of patient skin reaction. Such a relationship is not as clear as with other anti EGFR therapies, such as the EGFR-specific tyrosine kinase inhibitor, gefitinib, where efficacy appears to correlate with mutationshttp://www.bibsonomy.org/bibtex/2b235bf38116d96b265bbe73d55a047c1/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; A Adolescent Adult Aged Antibodies Antiphospholipid Cells Cultured Endothelial Enzyme Expression Factor Female Gene Growth Human Humans Imidazoles Inhibitors Kinase Kinases MAP Male Middle Mitogen-Activated Monocytes Phenotype Protein Pyridines Receptor-1 Regulation Research Signaling Syndrome System Thromboplastin Thrombosis Tyrosine Vascular antagonists biosynthesis cells drug effects inhibitors metabolism p38 pathology pharmacology protein <span class="authorEditorList"><a href="/author/Cuadrado">M. J. Cuadrado</a>, <a href="/author/Buendia">P. Buendia</a>, <a href="/author/Velasco">F. Velasco</a>, <a href="/author/Aguirre">M. A. Aguirre</a>, <a href="/author/Barbarroja">N. Barbarroja</a>, <a href="/author/Torres">L. A. Torres</a>, <a href="/author/Khamashta">M. Khamashta</a>, and <a href="/author/Lopez-Pedrera">C. Lopez-Pedrera</a> </span><em>J.Thromb.Haemost.</em> <em>4(11):2461-2469</em> (<em>2006</em>)Fri Feb 05 11:28:39 CET 2010J.Thromb.Haemost.112461-2469Vascular endothelial growth factor expression in monocytes from patients with primary antiphospholipid syndrome42006& A Adolescent Adult Aged Antibodies Antiphospholipid Cells Cultured Endothelial Enzyme Expression Factor Female Gene Growth Human Humans Imidazoles Inhibitors Kinase Kinases MAP Male Middle Mitogen-Activated Monocytes Phenotype Protein Pyridines Receptor-1 Regulation Research Signaling Syndrome System Thromboplastin Thrombosis Tyrosine Vascular antagonists biosynthesis cells drug effects inhibitors metabolism p38 pathology pharmacology protein BACKGROUND: One of the described mechanisms leading to thrombosis in antiphospholipid syndrome (APS) is overexpression of tissue factor (TF) in the monocytes and endothelial cells of patients with antiphospholipid antibodies (aPL). Vascular endothelial growth factor (VEGF) may stimulate monocyte TF expression through its receptor, the tyrosine kinase Flt-1. OBJECTIVES: This study aimed to analyze the following in monocytes of 55 primary APS patients: VEGF and Flt-1 expression levels, their potential regulation by aPL, and the association of VEGF and Flt-1 expression with the increased TF expression found in APS patients. RESULTS: Purified monocytes from APS patients showed higher levels of VEGF and Flt-1 than healthy donors, which further correlated with immunoglobulin G (IgG) anticardiolipin titers and TF expression rank. Moreover, monocyte VEGF and Flt-1 levels were significantly higher in patients with than in patients without previous thrombosis. In vitro, IgG from APS patients inchttp://www.bibsonomy.org/bibtex/28296f37e81a4e725fc9d421d2b2defe2/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Administration Adult Aged Agents Anthracyclines Antineoplastic Biological Breast Bridged Carcinoma Chemotherapy Combined Compounds Diseases Drug Fatigue Female Gastrointestinal Growth Hematologic Humans Indoles Inflammation Kinase Kinases Markers Middle Neoplasms Oral Plasma Protein-Tyrosine Protocols Pyrroles Rate Schedule Survival Taxoids Tumor Tyrosine administration adverse analysis antagonists blood chemically classification dosage drug effects induced inhibitors methods mortality response secondary therapeutic therapy use <span class="authorEditorList"><a href="/author/Burstein">H. J. Burstein</a>, <a href="/author/Elias">A. D. Elias</a>, <a href="/author/Rugo">H. S. Rugo</a>, <a href="/author/Cobleigh">M. A. Cobleigh</a>, <a href="/author/Wolff">A. C. Wolff</a>, <a href="/author/Eisenberg">P. D. Eisenberg</a>, <a href="/author/Lehman">M. Lehman</a>, <a href="/author/Adams">B. J. Adams</a>, <a href="/author/Bello">C. L. Bello</a>, <a href="/author/Deprimo">S. E. Deprimo</a>, <a href="/author/Baum">C. M. Baum</a>, and <a href="/author/Miller">K. D. Miller</a> </span><em>J Clin Oncol</em> <em>26(11):1810-1816</em> (<em>2008</em>)Fri Feb 05 11:28:39 CET 2010J Clin Oncol111810-1816Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane262008& Administration Adult Aged Agents Anthracyclines Antineoplastic Biological Breast Bridged Carcinoma Chemotherapy Combined Compounds Diseases Drug Fatigue Female Gastrointestinal Growth Hematologic Humans Indoles Inflammation Kinase Kinases Markers Middle Neoplasms Oral Plasma Protein-Tyrosine Protocols Pyrroles Rate Schedule Survival Taxoids Tumor Tyrosine administration adverse analysis antagonists blood chemically classification dosage drug effects induced inhibitors methods mortality response secondary therapeutic therapy use PURPOSE: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (KIT), and colony-stimulating factor-1 receptor. This phase II, open-label, multicenter study evaluated sunitinib monotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Sixty-four patients previously treated with an anthracycline and a taxane received sunitinib 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment). The primary end point was objective response rate. Plasma samples were obtained for pharmacokinetic and biomarker analysis. RESULTS: Seven patients achieved a partial response (median duration, 19 weeks), giving an overall response rate of 11%. Three additional patients (5%) maintained stable disease for >or= 6 months. Median time to progression and overall survival were 10 and 38 weeks, respectively. Notably, responses occurred in trhttp://www.bibsonomy.org/bibtex/28c7ec5956d78dd1114bd4d35a3eaeafd/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; Analysis Carcinoma Clinical DNA Drug Epidermal Factor Fluorescence Growth Humans Hybridization In Inhibitors Kinase Lung Mutation Mutational Neoplasm Neoplasms Non-Small-Cell Patient Population Protein Receptor Resistance Selection Situ Topic Trials Tyrosine analysis antagonists as drug genetics identify inhibitors protein response therapeutic therapy use <span class="authorEditorList"><a href="/author/Cappuzzo">F. Cappuzzo</a> </span><em>Lung Cancer</em> <em>60(2):160-165</em> (<em>2008</em>)Fri Feb 05 11:28:39 CET 2010Lung Cancer2160-165EGFR FISH versus mutation: different tests, different end-points602008& Analysis Carcinoma Clinical DNA Drug Epidermal Factor Fluorescence Growth Humans Hybridization In Inhibitors Kinase Lung Mutation Mutational Neoplasm Neoplasms Non-Small-Cell Patient Population Protein Receptor Resistance Selection Situ Topic Trials Tyrosine analysis antagonists as drug genetics identify inhibitors protein response therapeutic therapy use Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) demonstrated to significantly improve survival of non-small cell lung cancer patients (NSCLC) previously exposed to chemotherapy. Although clinical features, particularly smoking history, help physicians for identifying the sensitive population, a proper patient selection should not preclude to drug target assessment. EGFR mutations or increased EGFR gene copy number assessed by fluorescence in situ hybridization (FISH) identify NSCLC with the highest chance to respond to the therapy. Although indirect comparisons suggest that mutation analysis is the best available technique for identification of responders, survival improvement is not confined to individuals with tumor shrinkage. For patients with metastatic NSCLC, where definitive cure in not achievable, response is probably not the best end-point, since survival improvement observed with TKI included also patients with stable or progressive disease. Data from lhttp://www.bibsonomy.org/bibtex/2e1e0093a21e2bfab8ccf40b5087dc8ef/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; A Administration Adolescent Adult Aged Angiogenesis Biological Contrast Dose Dose-Response Drug Endothelial Factor Factors Fatigue Female Growth Human Humans Hypertension Imaging Inhibitors Kinase Magnetic Male Markers Maximum Media Medical Metastasis Middle Neoplasm Neoplasms Oncology Oral Outcome Pharmacokinetics Plasma Platelet-Derived Protein Proteins Proto-Oncogene Pyridazines Pyridines Receptor Receptor-2 Receptor-3 Relationship Research Resonance Safety Schedule Time Tolerated Treatment Tumor Tyrosine Vascular Young administration adverse antagonists beta blood c-kit diagnostic dosage drug effects enzymology inhibitors methods pathology protein response supply therapy toxicity use <span class="authorEditorList"><a href="/author/Eskens">F. A. Eskens</a>, <a href="/author/Steeghs">N. Steeghs</a>, <a href="/author/Verweij">J. Verweij</a>, <a href="/author/Bloem">J. L. Bloem</a>, <a href="/author/Christensen">O. Christensen</a>, <a href="/author/van">Doorn L. van</a>, <a href="/author/Ouwerkerk">J. Ouwerkerk</a>, <a href="/author/Jonge">M. J. Jonge</a>, <a href="/author/Nortier">J. W. Nortier</a>, <a href="/author/Kraetzschmar">J. Kraetzschmar</a>, <a href="/author/Rajagopalan">P. Rajagopalan</a>, and <a href="/author/Gelderblom">H. Gelderblom</a> </span><em>J.Clin.Oncol.</em> <em>27(25):4169-4176</em> (<em>2009</em>)Fri Feb 05 11:28:39 CET 2010J.Clin.Oncol.254169-4176Phase I dose escalation study of telatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet-derived growth factor receptor beta, and c-Kit, in patients with advanced or metastatic solid tumors272009& A Administration Adolescent Adult Aged Angiogenesis Biological Contrast Dose Dose-Response Drug Endothelial Factor Factors Fatigue Female Growth Human Humans Hypertension Imaging Inhibitors Kinase Magnetic Male Markers Maximum Media Medical Metastasis Middle Neoplasm Neoplasms Oncology Oral Outcome Pharmacokinetics Plasma Platelet-Derived Protein Proteins Proto-Oncogene Pyridazines Pyridines Receptor Receptor-2 Receptor-3 Relationship Research Resonance Safety Schedule Time Tolerated Treatment Tumor Tyrosine Vascular Young administration adverse antagonists beta blood c-kit diagnostic dosage drug effects enzymology inhibitors methods pathology protein response supply therapy toxicity use PURPOSE: Telatinib (BAY 57-9352) is an orally available tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor-beta, and c-Kit. This phase I dose escalation study was conducted to evaluate the safety and tolerability of telatinib, with additional pharmacokinetic, pharmacodynamic, and efficacy assessments. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Doses of continuously administered telatinib were escalated from 20 mg once daily to 1,500 mg twice daily. RESULTS: Fifty-three patients were enrolled. Most frequently observed drug-related adverse events were nausea (26.4%; grade >or= 3, 0%) and hypertension (20.8%; grade 3, 11.3%; grade 4, 0%). Two dose-limiting toxicities were observed: one poorly controlled hypertension (600 mg twice daily), and one grade 2 weight loss, anorexia, and fatigue (1,500 mg twice daily). A forhttp://www.bibsonomy.org/bibtex/2da3316c6e820f72389299eecdae161d6/kanefendtkanefendt2010-02-05T11:28:39+01:00&amp; 3 50 Angiogenesis Benzenesulfonates Bone Cell Cells Concentration Diseases Endothelial Factor Growth Hematologic Hematopoietic Human Humans Indoles Inhibitors Inhibitory Kinase Line Marrow Myelopoiesis Phosphorylation Platelet-Derived Protein Proteins Proto-Oncogene Pyridines Pyrimidines Pyrroles Receptors Research Specificity Stem Substrate Sulfonamides Tumor Tyrosine Vascular antagonists c-kit chemically drug effects enzymology fms-Like induced inhibitors methods pharmacology protein <span class="authorEditorList"><a href="/author/Kumar">R. Kumar</a>, <a href="/author/Crouthamel">M. C. Crouthamel</a>, <a href="/author/Rominger">D. H. Rominger</a>, <a href="/author/Gontarek">R. R. Gontarek</a>, <a href="/author/Tummino">P. J. Tummino</a>, <a href="/author/Levin">R. A. Levin</a>, and <a href="/author/King">A. G. King</a> </span><em>Br.J.Cancer</em> <em>101(10):1717-1723</em> (<em>2009</em>)Fri Feb 05 11:28:39 CET 2010Br.J.Cancer101717-1723Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors1012009& 3 50 Angiogenesis Benzenesulfonates Bone Cell Cells Concentration Diseases Endothelial Factor Growth Hematologic Hematopoietic Human Humans Indoles Inhibitors Inhibitory Kinase Line Marrow Myelopoiesis Phosphorylation Platelet-Derived Protein Proteins Proto-Oncogene Pyridines Pyrimidines Pyrroles Receptors Research Specificity Stem Substrate Sulfonamides Tumor Tyrosine Vascular antagonists c-kit chemically drug effects enzymology fms-Like induced inhibitors methods pharmacology protein BACKGROUND: Myelosuppression has been observed with several multikinase angiogenesis inhibitors in clinical studies, although the frequency and severity varies among the different agents. Inhibitors targeting vascular endothelial growth factor receptor (VEGFR) often inhibit other kinases, which may contribute to their adverse-event profiles. METHODS: Kinase selectivity of pazopanib, sorafenib, and sunitinib was evaluated in a panel of 242 kinases. Cellular potency was measured using autophosphorylation assays. Effect on human bone marrow progenitor growth in the presence of multiple growth factors was evaluated and correlated with the kinase selectivity. RESULTS: Sunitinib inhibited more kinases than pazopanib and sorafenib, at potencies within 10-fold of VEGFR-2. All three compounds potently inhibited VEGFR-2, platelet-derived growth factor receptor-beta and c-Kit, However, pazopanib was less active against Flt-3 in both kinase and cellular assays. The inhibitory properties of pazopan