Anti-metastatic activity of the tumor vascular targeting agent NGR-TNF

2015 ◽  
Vol 32 (3) ◽  
pp. 289-300 ◽  
Author(s):  
Paola Di Matteo ◽  
Patrizia Mangia ◽  
Elena Tiziano ◽  
Barbara Valentinis ◽  
Simona Porcellini ◽  
...  
Keyword(s):  
Vascular Targeting ◽  
Tumor Vascular Targeting ◽  
Metastatic Activity ◽  
Vascular Targeting Agent

The tumor vascular targeting agent combretastatin A–4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2060-2069 ◽  
Author(s):  
Chryso Kanthou ◽  
Gillian M. Tozer
Keyword(s):  
Endothelial Cells ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Focal Adhesions ◽  
Stress Fibers ◽  
Vascular Targeting ◽  
Microtubule Depolymerization ◽  
Functional Changes ◽  
Tumor Vascular Targeting ◽  
Vascular Targeting Agent

Abstract Combretastatin A–4-phosphate (CA-4-P) is a tubulin-binding compound currently in clinical trial as a tumor vascular-targeting agent. In endothelial cells, CA-4-P is known to cause microtubule depolymerization, but little is known about its subsequent effects on cell morphology and function. Here, we demonstrate that within minutes of endothelial cell exposure to CA-4-P, myosin light chain (MLC) was phosphorylated, leading to actinomyosin contractility, assembly of actin stress fibers, and formation of focal adhesions. These cytoskeletal alterations appeared to be a consequence of Rho activation, as they were abolished by either the Rho inhibitor C3 exoenzyme or Rho-kinase inhibitor Y-27632. In response to CA-4-P, some cells rapidly assumed a blebbing morphology in which F-actin accumulated around surface blebs, stress fibers misassembled into a spherical network surrounding the cytoplasm, and focal adhesions appeared malformed. Blebbing was associated with decreased cell viability and could be inhibited by Rho/Rho-kinase inhibitors or by blocking the CA-4-P–mediated activation of stress-activated protein kinase-2/p38. The extracellular-regulated kinases 1 and 2 (ERK-1/2) were shown to protect against blebbing since blebbing was attenuated on ERK-1/2 stimulation and was up-regulated by specific inhibition of ERK-1/2 activation. The use of MLC kinase (MLCK) and myosin adenosine triphosphatase inhibitors led us to propose a role for MLCK and myosin activity independent of MLC phosphorylation in regulating the blebbing process. CA-4-P–mediated contractility and blebbing were associated with a Rho-dependent increase in monolayer permeability to dextrans, suggesting that such functional changes may be important in the rapid response of the tumor endothelium to CA-4-P in vivo.

scholarly journals NGR-TNF, a novel vascular-targeting agent, does not induce cytokine recruitment of proangiogenic bone marrow-derived cells

2013 ◽  
Vol 109 (2) ◽  
pp. 360-369 ◽  
Author(s):  
P Di Matteo ◽  
C Hackl ◽  
C Jedeszko ◽  
B Valentinis ◽  
C Bordignon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vascular Targeting ◽  
Bone Marrow Derived Cells ◽  
Vascular Targeting Agent

ZD6126: A novel small molecule vascular targeting agent

2002 ◽  
Vol 54 (5) ◽  
pp. 1497-1502 ◽  
Author(s):  
David C Blakey ◽  
Susan E Ashton ◽  
F.Russell Westwood ◽  
Mike Walker ◽  
Anderson J Ryan
Keyword(s):  
Small Molecule ◽  
Vascular Targeting ◽  
Vascular Targeting Agent

Safety and anticancer activity of low dose regimen of NGRhTNF, a new vascular targeting agent, in solid advanced malignancies (NGR002 phase I trial)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3540-3540 ◽  
Author(s):  
C. Gallo-Stampino ◽  
G. Rizzardi ◽  
S. Toma ◽  
A. Corti ◽  
P. Scifo ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Vascular Permeability ◽  
Drug Exposure ◽  
Low Dose ◽  
Biological Effects ◽  
Cytotoxic Agents ◽  
Vascular Targeting ◽  
Frequent Event ◽  
Over Time ◽  
Vascular Targeting Agent

3540 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumours where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Methods: 4 dose levels of NGRhTNF (0.2 up to 1.6 mcg/sqm) have been administered q 3 w in 16 patients. Main end-points included safety, anticancer activity and pharmacokinetic.Measurement of circulating tumor and endothelial cells (CTC and CEC), sTNFRI and s TNFRII, along with plasma cyto-chemokine profile have been performed. Results: 16 patients were enrolled (6F/10M);median age 60,range 43–73). Toxicity was limited to constitutional symptoms, and chills were the most frequent event (40%). Over a median follow-up of 15 weeks, stable disease was achieved in 44% of patients, with long lasting disease control in 2 cases (27 and 75 weeks, with establishment of indication to radical surgery after 75 weeks, presently tumor free after removal of the residual tumor mass). In these 2 patients, VEGF, MMP-9, CA125, significantly decreased over time. DCE-MRI indicates that NGRhTNF increases vascular permeability after first drug exposure, particularly at the dose of 0.4 mcg/sqm, while following multiple infusions it exerts an antivascular effect, as demonstrated by the decrease of Ktrans values. Moreover NGRhTNF is able to elicit inflammatory and immune responses over time, as indicated by the modulation of expression of multiple cyto-chemokines. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Low dose NGRhTNF has an optimal safety profile along with anticancer activity acting on tumour vasculature and inducing relevant biological effects, thus rendering the agent suitable for a development both as monotherapy and in combination with chemotherapeutics. The phase II program is due to start in early 2007. [Table: see text]

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