Open AccessJournal Article
In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet-derived Growth Factor Receptors Determination of a Pharmacokinetic/Pharmacodynamic Relationship
Dirk B. Mendel,A. Douglas Laird,Xiaohua Xin,Sharianne G. Louie,James G. Christensen,Guangmin Li,Randall E. Schreck,Tinya Abrams,Theresa J. Ngai,Leslie Lee,Lesley J. Murray,Jeremy P. Carver,Emily Chan,Katherine G. Moss,Joshua Ö. Haznedar,Juthamas Sukbuntherng,Robert A. Blake,Li Sun,Cho Tang,Todd W. Miller,Sheri Shirazian,Gerald Mcmahon,Julie M. Cherrington +22 more
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TLDR
The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.Abstract:
One challenging aspect in the clinical development of molecularly targeted therapies, which represent a new and promising approach to treating cancers, has been the identification of a biologically active dose rather than a maximum tolerated dose. The goal of the present study was to identify a pharmacokinetic/pharmacodynamic relationship in preclinical models that could be used to help guide selection of a clinical dose. SU11248, a novel small molecule receptor tyrosine kinase inhibitor with direct antitumor as well as antiangiogenic activity via targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), KIT, and FLT3 receptor tyrosine kinases, was used as the pharmacological agent in these studies. In mouse xenograft models, SU11248 exhibited broad and potent antitumor activity causing regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. To predict the target SU11248 exposure required to achieve antitumor activity in mouse xenograft models, we directly measured target phosphorylation in tumor xenografts before and after SU11248 treatment and correlated this with plasma inhibitor levels. In target modulation studies in vivo , SU11248 selectively inhibited Flk-1/KDR (VEGF receptor 2) and PDGF receptor β phosphorylation (in a time- and dose-dependent manner) when plasma concentrations of inhibitor reached or exceeded 50–100 ng/ml. Similar results were obtained in a functional assay of VEGF-induced vascular permeability in vivo . Constant inhibition of VEGFR2 and PDGF receptor β phosphorylation was not required for efficacy; at highly efficacious doses, inhibition was sustained for 12 h of a 24-h dosing interval. The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.read more
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Axitinib in the treatment of metastatic renal cell carcinoma
Thai H. Ho,Eric Jonasch +1 more
TL;DR: Axitinib, an oral small-molecule tyrosine kinase inhibitor targeted to angiogenesis, has demonstrated activity in advanced renal cell carcinoma and trials are ongoing and will study the benefit of axitinib in the first-line setting.
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Trans-inhibition of activation and proliferation signals by Fc receptors in mast cells and basophils
Odile Malbec,Odile Malbec,Lydie Cassard,Lydie Cassard,Marcello Albanesi,Marcello Albanesi,Friederike Jönsson,Friederike Jönsson,David A. Mancardi,David A. Mancardi,Gaëtan Chicanne,Gaëtan Chicanne,Bernard Payrastre,Bernard Payrastre,Patrice Dubreuil,Eric Vivier,Marc Daëron,Marc Daëron,Marc Daëron +18 more
TL;DR: The data suggest that trans-inhibition controls numerous physiological and pathological processes, and that it may be used as a therapeutic tool in inflammation, especially but not exclusively, in allergy and autoimmunity.
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Imidazo[1,2-a]pyrazine diaryl ureas: inhibitors of the receptor tyrosine kinase EphB4.
Scott A. Mitchell,Mihaela Diana Danca,Peter Blomgren,James W. Darrow,Kevin S. Currie,Kropf Jeffrey E,Seung H. Lee,Steven L. Gallion,Jin-Ming Xiong,Douglas A. Pippin,Robert Desimone,David R. Brittelli,David C. Eustice,Aaron Bourret,Melissa Hill-Drzewi,Patricia Maciejewski,Lisa Elkin +16 more
TL;DR: A novel series of imidazo[1,2-a]pyrazine diarylureas that show nanomolar potency for the EphB4 receptor, in addition to potent activity against several other RTKs are reported.
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Molecularly targeted therapies in unresectable-metastatic gastric cancer: a systematic review.
TL;DR: This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic gastric cancer.
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Risk of hypothyroidism in patients with cancer treated with sunitinib: a systematic review and meta-analysis.
TL;DR: A meta-analysis of data available from clinical trials demonstrates that sunitinib is associated with a significant risk of developing all- and high-grade hypothyroidism.
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