Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway

<p>Abstract</p> <p>Background</p> <p>The antiangiogenic agent cilengitide disrupts integrin binding to the extracellular matrix leading to apoptosis of activated endothelial cells. Integrins are also widely expressed in malignant glioma and integrin inhibitors may directly target tumor cells in this disease. Aim of the current study was to investigate effects of cilengitide on endothelial and glioma cells on molecular and cellular levels.</p> <p>Results</p> <p>Cilengitide caused dose-dependent detachment of endothelial cells from cell culture dishes. Proliferation of endothelial cells was significantly inhibited while the proportion of apoptotic cells was increased. Incubation of integrin-expressing glioma cells with cilengitide caused rounding and detachment after 24 hours as observed with endothelial cells. Cilengitide inhibited proliferation and induced apoptosis in glioma cells with methylated MGMT promotor when given alone or in combination with temozolomide. In endothelial as well as glioma cells cilengitide inhibited phosphorylation of FAK, Src and Akt. Assembly of cytoskeleton and tight junctions was heavily disturbed in both cell types.</p> <p>Conclusion</p> <p>Cilengitide inhibits integrin-dependent signaling, causes disassembly of cytoskeleton, cellular detachment and induction of apoptosis in endothelial and glioma cells thereby explaining the profound activity of integrin inhibitors in gliomas. The combination of cilengitide with temozolomide exerted additive effects in glioma cells as observed clinically.</p

484pretrospective ras analysis of the epic trial cetuximab plus irinotecan vs irinotecan in patients pts with second line metastatic colorectal cancer mcrc

n/

Cetuximab in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) in the initial treatment of metastatic colorectal cancer: a multicentre two-part phase I/II study

This study was designed to investigate the efficacy and safety of the epidermal growth factor receptor (EGFR) inhibitor cetuximab combined with irinotecan, folinic acid (FA) and two different doses of infusional 5-fluorouracil (5-FU) in the first-line treatment of EGFR-detectable metastatic colorectal cancer.Clinical Trial, Phase IClinical Trial, Phase IIJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Spatial organisation of groundwater dynamics and streamflow response from different hydropedological units in a montane catchment

Funding was provided by the Leibniz Association (SAW-2012-IGB 4167) within the International Leibniz Graduate School: Aquatic boundaries and linkages- Aqualink. We would like to thank the NRI staff for their help during field work.Peer reviewedPostprin

Identifying streamgage networks for maximizing the effectiveness of regional water balance modeling

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98795/1/wrcr20233.pd

A phase II study of a human anti-PDGFR alpha monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors

Experimentele farmacotherapi

A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer

BACKGROUND: Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. METHODS: A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m(2 )twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m(2 )for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. RESULTS: Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. CONCLUSION: There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent

Origine et époque des emprunts d'anciens mots germaniques par les langues finnoises baltiques

Nippgen J. Origine et époque des emprunts d'anciens mots germaniques par les langues finnoises baltiques. In: Bulletins et Mémoires de la Société d'anthropologie de Paris, V° Série. Tome 8, 1907. pp. 179-203