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Aflibercept.
Ciombor KK, Berlin J, Chan E
(2013) Clin Cancer Res 19: 1920-5
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, Disease-Free Survival, Fluorouracil, Humans, Irinotecan, Leucovorin, Neoplasm Metastasis, Organoplatinum Compounds, Oxaliplatin, Placenta Growth Factor, Pregnancy Proteins, Protein Binding, Randomized Controlled Trials as Topic, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Treatment Outcome, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor B
Show Abstract · Added September 10, 2013
Aflibercept, an intravenously administered anti-VEGF and antiplacental growth factor (PlGF) agent, has recently been approved by the U.S. Food and Drug Administration in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer who have previously received an oxaliplatin-containing chemotherapy regimen. In the phase III VELOUR trial, aflibercept plus FOLFIRI statistically significantly prolonged both progression-free survival (PFS; median PFS for the aflibercept plus FOLFIRI arm was 6.90 vs. 4.67 months for the placebo-plus-FOLFIRI arm) and overall survival (median overall survival for the aflibercept-plus-FOLFIRI arm was 13.50 vs. 12.06 months for the placebo plus FOLFIRI arm), but grade 3 or 4 adverse events were more common with the addition of aflibercept. However, the addition of aflibercept to 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in the phase II AFFIRM trial of first-line treatment of mCRC failed to improve PFS or response rate. As a decoy VEGF receptor, aflibercept (VEGF-Trap) has binding affinity for VEGF-A, VEGF-B, PlGF-1, and PlGF-2, and this is a mechanism of significant interest. Optimal strategies for incorporating aflibercept into treatment regimens that include other anti-VEGF and cytotoxic chemotherapeutic agents, as well as development of predictive biomarkers for treatment response, have yet to be defined.
0 Communities
4 Members
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22 MeSH Terms
Vascular tissues are a primary source of BMP2 expression during bone formation induced by distraction osteogenesis.
Matsubara H, Hogan DE, Morgan EF, Mortlock DP, Einhorn TA, Gerstenfeld LC
(2012) Bone 51: 168-80
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Cell Differentiation, Male, Mice, Mice, Transgenic, Osteogenesis, Osteogenesis, Distraction, Placenta Growth Factor, Pregnancy Proteins, Vascular Endothelial Growth Factor A, beta-Galactosidase
Show Abstract · Added May 27, 2014
Prior studies showed that bone regeneration during distraction osteogenesis (DO) was dependent on vascular tissue development and that inhibition of VEGFR signaling diminished the expression of BMP2. A combination of micro-computed tomography (μCT) analysis of vascular and skeletal tissues, immunohistological and histological analysis of transgenic mice containing a BAC transgene in which β-galactosidase had been inserted into the coding region of BMP2 and qRT-PCR analysis, was used to examine how the spatial temporal expression of the morphogenetic signals that drive skeletal and vascular tissue development is coordinated during DO. These results showed that BMP2 expression was induced in smooth muscle and vascular endothelial cells of arteries and veins, capillary endothelial cells, hypertrophic chondrocytes and osteocytes. BMP2 was not expressed by lymphatic vessels or macrophages. Separate peaks of BMP2 mRNA expression were induced in the surrounding muscular tissues and the distraction gap and corresponded first with large vessel collateralization and arteriole remodeling followed by periods of angiogenesis in the gap region. Immunohistological and qRT-PCR analysis of VEGF receptors and ligands showed that mesenchymal cells, lining cells and chondrocytes, expressed VEGFA, although PlGF expression was only seen in mesenchymal cells within the gap region. On the other hand VEGFR2 appeared to be predominantly expressed by vascular endothelial and hematopoietic cells. These results suggest that bone and vascular tissue formation is coordinated via a mutually supporting set of paracrine loops in which blood vessels primarily synthesize the morphogens that promote bone formation while mesenchymal cells primarily synthesize the morphogens that promote vascular tissue formation.
Copyright © 2012 Elsevier Inc. All rights reserved.
2 Communities
1 Members
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12 MeSH Terms
The vascular marker soluble fms-like tyrosine kinase 1 is associated with disease severity and adverse outcomes in chronic heart failure.
Ky B, French B, Ruparel K, Sweitzer NK, Fang JC, Levy WC, Sawyer DB, Cappola TP
(2011) J Am Coll Cardiol 58: 386-94
MeSH Terms: Aged, Biomarkers, Female, Heart Failure, Humans, Male, Middle Aged, Placenta Growth Factor, Pregnancy Proteins, Severity of Illness Index, Vascular Endothelial Growth Factor Receptor-1
Show Abstract · Added May 28, 2014
OBJECTIVES - We sought to evaluate placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) as clinical biomarkers in chronic heart failure (HF).
BACKGROUND - Vascular remodeling is a crucial compensatory mechanism in chronic HF. The angiogenic ligand PlGF and its target receptor fms-like tyrosine kinase 1 modulate vascular growth and function, but their relevance in human HF is undefined.
METHODS - We measured plasma PlGF and sFlt-1 in 1,403 patients from the Penn Heart Failure Study, a multicenter cohort of chronic systolic HF. Subjects were followed for death, cardiac transplantation, or ventricular assist device placement over a median follow-up of 2 years.
RESULTS - The sFlt-1 was independently associated with measures of HF severity, including New York Heart Association functional class (p < 0.01) and B-type natriuretic peptide (p < 0.01). Patients in the 4th quartile of sFlt-1 (>379 pg/ml) had a 6.17-fold increased risk of adverse outcomes (p < 0.01). This association was robust, even after adjustment for the Seattle Failure Model (hazard ratio: 2.54, 95% confidence interval [CI]: 1.76 to 2.27, p < 0.01) and clinical confounders including HF etiology (hazard ratio: 1.67, 95% CI: 1.06 to 2.63, p = 0.03). Combined assessment of sFlt-1 and B-type natriuretic peptide exhibited high predictive accuracy at 1 year (area under the receiver-operator characteristic curve: 0.791, 95% CI: 0.752 to 0.831) that was greater than either marker alone (p < 0.01 and p = 0.03, respectively). In contrast, PlGF was not an independent marker of disease severity or outcomes.
CONCLUSIONS - Our findings support a role for sFlt-1 in the biology of human HF. With additional study, circulating sFlt-1 might emerge as a clinically useful biomarker to assess the influence of vascular remodeling on clinical outcomes.
Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms
Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma.
Rini BI, Michaelson MD, Rosenberg JE, Bukowski RM, Sosman JA, Stadler WM, Hutson TE, Margolin K, Harmon CS, DePrimo SE, Kim ST, Chen I, George DJ
(2008) J Clin Oncol 26: 3743-8
MeSH Terms: Administration, Oral, Adult, Aged, Angiogenesis Inhibitors, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Bevacizumab, Biomarkers, Tumor, Carcinoma, Renal Cell, Disease-Free Survival, Drug Administration Schedule, Drug Resistance, Neoplasm, Female, Humans, Indoles, Kidney Neoplasms, Male, Middle Aged, Placenta Growth Factor, Pregnancy Proteins, Prospective Studies, Pyrroles, Sunitinib, Time Factors, Treatment Failure, United States, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor Receptor-3
Show Abstract · Added March 20, 2014
PURPOSE - To assess the safety and efficacy of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma (mRCC) and explore biomarkers for sunitinib response.
PATIENTS AND METHODS - Patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6-week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment) in a phase II multicenter study. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), duration of response (DR), overall survival (OS), and safety. Plasma soluble proteins (vascular endothelial growth factor [VEGF]-A, VEGF-C, soluble VEGF receptor [sVEGFR]-3, and placental growth factor [PlGF]) levels were measured.
RESULTS - Sixty-one patients were enrolled. The ORR was 23.0% (95% CI, 13.2% to 35.5%), median PFS was 30.4 weeks (95% CI, 18.3 to 36.7 weeks), median DR was 44.1 weeks (95% CI, 25.0 to 102.7 weeks), and median OS was 47.1 weeks (95% CI, 36.9 to 79.4 weeks). Mean plasma VEGF-A and PlGF levels significantly increased whereas VEGF-C and sVEGFR-3 levels decreased with sunitinib treatment. Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS and ORR. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome.
CONCLUSION - Sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC and modulates circulating VEGF pathway biomarkers. These data support the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance. Baseline levels of sVEGFR-3 and VEGF-C may have potential utility as biomarkers of clinical efficacy in this setting.
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29 MeSH Terms
Angiotensin converting enzyme inhibitor but not angiotensin receptor blockade or statin ameliorates murine adriamycin nephropathy.
Tang SC, Leung JC, Chan LY, Eddy AA, Lai KN
(2008) Kidney Int 73: 288-99
MeSH Terms: Angiotensin II, Angiotensin II Type 1 Receptor Blockers, Angiotensin-Converting Enzyme Inhibitors, Animals, Cell Proliferation, Cells, Cultured, Chemokine CCL2, Collagen Type I, Doxorubicin, Drug Therapy, Combination, Epithelial Cells, Glomerulosclerosis, Focal Segmental, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Kidney, Macrophages, Mice, Mice, Inbred BALB C, Peptidyl-Dipeptidase A, Phenotype, Placenta Growth Factor, Pregnancy Proteins, Signal Transduction, Transforming Growth Factor beta
Show Abstract · Added February 3, 2012
Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins have renoprotective effects. We studied the cellular mechanisms for this effect in adriamycin-treated mice receiving captopril, losartan, simvastatin, or their combinations. The mice developed albuminuria, renal insufficiency, and parenchymal inflammation/fibrosis accompanied by overexpression of intrarenal converting enzyme and angiotensin II. Only captopril consistently improved these abnormalities and reduced the cortical expression of several proinflammatory and profibrotic factors including transforming growth factor-beta (TGF-beta). These effects were independent of blood pressure, accompanied by increased urine N-acetylseryl-aspartyl-lysyl-proline (Ac-SDKP) levels, and the restoration of renal angiotensin-converting enzyme and angiotensin II to baseline levels. Losartan or simvastatin alone or together had no effect, and their addition to captopril did not enhance protection. In vitro, angiotensin II stimulated TGF-beta in renal tubular cells via mitogen-activated protein kinase (MAPK) signaling. Captopril or Ac-SDKP suppressed angiotensin II-induced MAPK activation and TGF-beta secretion. Angiotensin-converting enzyme inhibition confers renoprotection in adriamycin nephropathy by reducing intrarenal angiotensin II and augmenting Ac-SDKP expression that together attenuate MAPK signaling and its downstream proinflammatory and fibrogenic properties. The addition of receptor blocker and/or statin failed to potentiate such effects.
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1 Members
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24 MeSH Terms