Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C1519670 (tumor angiogenesis)
6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastatic renal cell carcinoma does not respond favorably to conventional treatment strategies and is not very responsive to cytokine therapy. Therefore, novel targeted treatment approaches have been explored for patients with renal cancer who have chemotherapy-refractory disease. Sorafenib (BAY 43-9006) is a small-molecule inhibitor that has been shown to target members of multiple classes of tyrosine kinases that are known to be involved in tumor cell proliferation and tumor angiogenesis. These kinases include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and Raf kinases. Based on the significant improvement in progression-free survival, sorafenib received Food and Drug Administration approval in December 2005 for the treatment of renal cell carcinoma. In combination studies, sorafenib with other antitumor agents has demonstrated significant clinical activity in patients with renal cell carcinoma. As discussed in this mini-review, the clinical potency of sorafenib as a single agent or in combination with other antitumor agents is being evaluated in several ongoing clinical trials in patients with renal carcinoma.
...
PMID:Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma. 1672 6

Activating mutations in Ras and B-RAF were identified in several human cancers. In addition, several receptor tyrosine kinases, acting upstream of Ras, were found either mutated or overexpressed in human tumors. Because oncogenic activation of the Ras/RAF pathway may lead to a sustained proliferative signal resulting in tumor growth and progression, inhibition of this pathway represents an attractive approach for cancer drug discovery. A novel class of biaryl urea that inhibits C-RAF kinase was discovered using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). It inhibited MEK and ERK phosphorylation in various cancer cell lines and tumor xenografts and exhibited potent oral antitumor activity in a broad spectrum of human tumor xenograft models. Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. Thus, sorafenib may inhibit tumor growth by a dual mechanism, acting either directly on the tumor (through inhibition of Raf and Kit signaling) and/or on tumor angiogenesis (through inhibition of VEGFR and PDGFR signaling). In phase I and phase II clinical trials, sorafenib showed limited side effects and, more importantly, disease stabilization. This agent is currently being evaluated in phase III clinical trials in renal cell and hepatocellular carcinomas.
...
PMID:Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. 1675 55

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) plays a critical role in transcriptional gene activation involved in tumor angiogenesis. A novel class of agents, the histone deacetylase (HDAC) inhibitors, has been shown to inhibit tumor angiogenesis and HIF-1 alpha protein expression. However, the molecular mechanism responsible for this inhibition remains to be elucidated. In the current study, we investigated the molecular link between HIF-1 alpha inhibition and HDAC inhibition. Treatment of the VHL-deficient human renal cell carcinoma cell line UMRC2 with the hydroxamic HDAC inhibitor LAQ824 resulted in a dose-dependent inhibition of HIF-1 alpha protein via a VHL-independent mechanism and reduction of HIF-1 alpha transcriptional activity. HIF-1 alpha inhibition by LAQ824 was associated with HIF-1 alpha acetylation and polyubiquitination. HIF-1 alpha immunoprecipitates contained HDAC activity. Then, we tested different classes of HDAC inhibitors with diverse inhibitory activity of class I versus class II HDACs and assessed their capability of targeting HIF-1 alpha. Hydroxamic acid derivatives with known activity against both class I and class II HDACs were effective in inhibiting HIF-1 alpha at low nanomolar concentrations. In contrast, valproic acid and trapoxin were able to inhibit HIF-1 alpha only at concentrations that are effective against class II HDACs. Coimmunoprecipitation studies showed that class II HDAC4 and HDAC6 were associated with HIF-1 alpha protein. Inhibition by small interfering RNA of HDAC4 and HDAC6 reduced HIF-1 alpha protein expression and transcriptional activity. Taken together, these results suggest that class II HDACs are associated with HIF-1 alpha stability and provide a rationale for targeting HIF-1 alpha with HDAC inhibitors against class II isozymes.
...
PMID:Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. 1695 Nov 98

Over the last few years, renal cell carcinoma (RCC) has become a model disease for targeted therapeutics based on the growing understanding of the underlying molecular pathways in this disease. Clear cell RCC is characterized by the inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene, which results in the dysregulation of hypoxia response genes, including an overproduction of vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis, growth, and metastasis. In advanced RCC, substantial clinical activity has been reported with VEGF blockade employing a variety of approaches including antibodies and small-molecule VEGF receptor inhibitors. Many trials are still in progress with the goal of defining the optimal utility of these agents as monotherapy or in combination. This review will describe the current clinical data with VEGF-targeted approaches in RCC and plans for future development.
...
PMID:The current role of angiogenesis inhibitors in the treatment of renal cell carcinoma. 1704 89

Recently, pegylated arginine deiminase (ADI; EC 3.5.3.6) has been used to treat the patients with hepatocellular carcinoma or melanoma, in which the level of argininosuccinate synthetase (ASS) activity is low or undetectable. The efficacy of its antitumor activity largely depends on the level of intracellular ASS, which enables tumor cells to recycle citrulline to arginine. Thus, we examined the expression levels of ASS in various cancer cells and found that it is low in renal cell carcinoma (RCC) cells, rendering the cells highly sensitive to arginine deprivation by ADI treatment. Immunohistochemical analysis revealed that in biopsy specimens from RCC patients (n = 98), the expression of ASS is highly demonstrated in the epithelium of normal proximal tubule but not seen in tumor cells. Furthermore, RCC cells treated with ADI showed remarkable growth retardation in a dose dependent manner. ADI also exerted in vivo antiproliferative effect on the allografted renal cell carcinoma (RENCA) tumor cells and prolonged the survival of tumor-bearing mice. Histological examination of the tumors revealed that tumor angiogenesis and vascular endothelial growth factor (VEGF) expression were significantly diminished by ADI administration. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of RCC in ways of inhibitions of arginine availability and neovascularization.
...
PMID:Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase. 1709 30

Recently, there has been a growing interest in understanding the role of receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), in promoting tumor angiogenesis, tumor growth and metastasis. Sunitinib (sunitinib malate; SU11248; SUTENT; Pfizer Inc, New York, NY, USA) is a novel, orally bio-available, oxindole, multi-targeted tyrosine kinase inhibitor with high binding affinity for VEGFR and PDGFR which has shown anti-tumor and anti-angiogenic activities. This drug recently received approval from the US Food and Administration (FDA) in two indications simultaneously: advanced renal cell carcinoma (adRCC) and gastrointestinal stromal tumors (GIST), in patients who are resistant or intolerant to the treatment with imatinib. The present article reviews the recent pharmacologic and clinical data related to the use of this new promising drug in the field of oncology.
...
PMID:Sunitinib malate. 1713 43

Clear-cell renal cell carcinoma is characterized by the inactivation of the von Hippel-Lindau tumor suppressor gene, which results in an overproduction of vascular endothelial growth factor that promotes tumor angiogenesis, growth, and metastasis after binding with its receptor. The mammalian target of rapamycin signal transduction pathway is involved in the translation of hypoxia inducible factor-1 and vascular endothelial growth factor. Sunitinib, sorafenib, bevacizumab, and temsirolimus have improved clinical outcomes by inhibiting these tumorigenic pathways. Other multitargeted tyrosine kinase inhibitors (lapatinib, axitinib, pazopanib) and antiangiogenic agents (lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. Clinical trials designed to further assess these and other agents need to be vigorously supported.
...
PMID:Targeting growth factor and antiangiogenic pathways in clear-cell renal cell carcinoma: rationale and ongoing trials. 1723 82

Frequent loss of the von Hippel-Lindau (VHL) gene product in conventional-type renal cell carcinoma results in constitutive expression of proangiogenic growth factors, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). VEGF and PDGF function in a paracrine manner to stimulate tumor angiogenesis that results in a hypervascular phenotype. Dependency on this hypervascularity is underscored by the recent clinical efficacy shown by inhibition of the VEGF pathway. Most strategies that primarily target the VEGF pathway (neutralizing antibodies or receptor tyrosine kinase inhibitors) result in objective tumor responses in < or =10% of cases but show a significant delay in time to disease progression. In contrast, two multitargeted receptor tyrosine kinase inhibitors that target both VEGF and PDGF receptors (sunitinib and AG013736) have shown > or =40% objective responses with clinically important duration. Several hypotheses may explain the discrepancy of these response rates from other strategies in the class, including the synergistic effects of dual inhibition of VEGF and PDGF receptors, supported by preclinical studies. Ultimately, further clinical investigations with pharmacodynamic and correlative science end points are needed to clarify the mechanisms of action and resistance to build on the biological and clinical effects of these multitargeted agents.
...
PMID:Phase 2 studies of sunitinib and AG013736 in patients with cytokine-refractory renal cell carcinoma. 1725 5

Traditional cross-sectional tumor imaging focuses solely on tumor morphology. With the introduction of targeted biological therapies in human trials, morphologic change may lag behind other physiologic measures of response on clinical images. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a new imaging method for assessing the physiologic state of tumor vascularity in vivo. DCE-MRI, which uses available imaging techniques and contrast agents, assays the kinetics of tumor enhancement during bolus i.v. contrast administration. Modeling of the temporal enhancement pattern yields physiologic variables related to tumor blood flow and microvessel permeability. Changes in these variables after vascular-targeted therapy can then be quantified to evaluate the tumor vascular response. As these responses may precede morphologic tumor shrinkage, DCE-MRI might serve as a noninvasive means of monitoring early tumor response to vascular-targeted therapy. Renal cell carcinoma provides an excellent model for assessing the effect on DCE-MRI in clinical trials. The vascular richness of renal tumors provides a large dynamic scale of DCE-MRI measures. Patients with disseminated renal cell carcinoma frequently present with one or several large tumors, creating an easy imaging target for DCE-MRI evaluation. Finally, renal cell carcinoma is clearly susceptible to therapies that target tumor angiogenesis. DCE-MRI can be used to monitor the vascular changes induced by such therapies. Future efforts must be directed to standardizing image acquisition and analysis techniques to quantify tumor vascular responses.
...
PMID:Dynamic contrast-enhanced magnetic resonance imaging for assessing tumor vascularity and vascular effects of targeted therapies in renal cell carcinoma. 1725 8

Angiogenesis or the development of new blood vessels from the surrounding vasculature is essential for the growth and progression of solid tumors. Vascular endothelial growth factor (VEGF), a positive regulator of angiogenesis, plays a pivotal role in tumor angiogenesis and shows a high expression in almost all known tumors, including transitional cell carcinoma (TCC) of the bladder. A novel isoform, VEGF(165)b containing a novel exon 9, was recently identified in renal cell carcinoma and was shown to be down-regulated and inhibitory in nature. We aimed to analyze quantitatively expression of this isoform, VEGF(165)b, in TCC of the bladder and compare it to the benign part of the same organ. A real-time reverse transcriptase polymerase chain reaction protocol was set up to quantitate simultaneously the messenger ribonucleic acid levels of VEGF and VEGF(165)b from 34 clinical samples representing bladder cancer and matched benign tissue. Expression of VEGF(165)b showed a >or=3.0-fold change in 27 of 34 (79%) bladder tumors than the benign samples. Increased expression of VEGF(165)b was seen in superficial tumors as compared to invasive tumors, which was statistically significant (P < 0.001). Therefore, VEGF(165)b was up-regulated in TCC of the bladder.
...
PMID:Differential expression of vascular endothelial growth factor165b in transitional cell carcinoma of the bladder. 1762 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---