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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
Analytical aspects of sunitinib and its geometric isomerism towards therapeutic drug monitoring in clinical routine.
Bianca Posocco,Mauro Buzzo,Luciana Giodini,Sara Crotti,Sara D'Aronco,Pietro Traldi,Marco Agostini,Elena Marangon,Giuseppe Toffoli +8 more
TL;DR: A simple and fast procedure was setup to quantitatively reconvert the E‐isomer formed during sample collection and processing without light protection into its Z‐form thus leading to a single peak to quantify, and this additional step allows to develop a LC–MS/MS method suitable to clinical practice.
Journal ArticleDOI
Anti-angiogenesis approach to genitourinary cancer treatment
TL;DR: The biologic pathways as well as the rationale for using angiogenesis inhibitors in renal cell, prostate, and transitional cell bladder cancers are discussed and pivotal trials and emerging data on the use of these inhibitors are focused on.
Journal ArticleDOI
Evolving therapies in the treatment of hepatocellular carcinoma.
TL;DR: This review gives an overview of the current therapeutic strategies and their clinical impact in patients with advanced HCC.
Journal ArticleDOI
A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours.
Epie Boven,Christophe Massard,J.P. Armand,C N Tillier,V Hartog,N M Brega,A M Countouriotis,Ana Ruiz-Garcia,J-C. Soria +8 more
TL;DR: Although a higher sunitinib dose of 37.5 mg per day with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated and this particular combination will not be pursued for further studies.
Journal ArticleDOI
Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions.
TL;DR: The development of new targeted therapies including axitinib, pazopanib, cediranIB, volociximab, tivozanab, and c-met inhibitors may potentially expand the list of treatment options for RCC.
References
More filters
Journal ArticleDOI
The hallmarks of cancer.
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
Journal ArticleDOI
Cell signaling by receptor-tyrosine kinases
TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
Journal ArticleDOI
Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo.
TL;DR: It is shown that expression of an endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), is induced in astrocytoma cells but is dramatically upregulated in two apparently different subsets of glioblastoma cells, which strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify VEGF as a potential tumourAngiogenesis factor in vivo.
Journal ArticleDOI
Signaling by Receptor Tyrosine Kinases
TL;DR: The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane gly-coprotein tyrosine receptor kinases (RTK) and stimulates intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival.
Journal ArticleDOI
Molecular and biological properties of vascular endothelial growth factor.
TL;DR: Current evidence indicates that VEGF is essential for embryonic vasculogenesis and angiogenesis, and both therapeuticAngiogenesis using recombinant V EGF or VEGFs gene transfer and inhibition of VEGf-mediated pathological angiogenic are being pursued.
Related Papers (5)
BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis
Scott Wilhelm,Christopher A. Carter,LiYa Tang,Dean Wilkie,Angela McNabola,Hong Rong,Charles Chen,Xiaomei Zhang,Patrick Vincent,Mark McHugh,Yichen Cao,Jaleel Shujath,Susan Gawlak,Deepa Eveleigh,Bruce Rowley,Li Liu,Lila Adnane,Mark Lynch,Daniel Auclair,Ian W. Taylor,Rich Gedrich,Andrei Voznesensky,Bernd Riedl,Leonard Post,Gideon Bollag,Pamela A. Trail +25 more