Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation.
Abstract
Elevated intratumoral interstitial fluid pressure (IFP) and tumour hypoxia are independent
predictive factors for poor survival and poor treatment response in cancer patients.
However, the relationship between IFP and tumour hypoxia has not yet been clearly
established. Preclinical studies have shown that lowering IFP improves treatment response
to cytotoxic therapy. Interstitial fluid pressure can be reduced by inhibition of
phosphorylated platelet-derived growth factor receptor-beta (p-PDGFR-beta), a tyrosine
kinase receptor frequently overexpressed in cancer stroma, and/or by inhibition of
VEGF, a growth factor commonly overexpressed in tumours overexpressing p-PDGFR-beta.
We hypothesised that Imatinib, a specific PDGFR-beta inhibitor will, in addition to
p-PDGFR-beta inhibition, downregulate VEGF, decrease IFP and improve tumour oxygenation.
A549 human lung adenocarcinoma xenografts overexpressing PDGFR-beta were grown in
nude mice. Tumour-bearing animals were randomised to control and treatment groups
(Imatinib 50 mg kg(-1) via gavage for 4 days). Interstitial fluid pressure was measured
in both groups before and after treatment. EF5, a hypoxia marker, was administered
3 h before being killed. Tumours were sectioned and stained for p-PDGFR-beta, VEGF
and EF5 binding. Stained sections were viewed with a fluorescence microscope and image
analysis was performed. Imatinib treatment resulted in significant reduction of p-PDGFR-beta,
VEGF and IFP. Tumour oxygenation was also significantly improved. This study shows
that p-PDGFR-beta-overexpressing tumours can be effectively treated with Imatinib
to decrease tumour IFP. Importantly, this is the first study demonstrating that Imatinib
treatment improves tumour oxygenation and downregulates tumour VEGF expression.
Type
Journal articleSubject
AdenocarcinomaAnimals
Antineoplastic Agents
Benzamides
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Extracellular Fluid
Female
Humans
Imatinib Mesylate
Immunohistochemistry
Lung Neoplasms
Mice
Mice, Nude
Microscopy, Fluorescence
Models, Biological
Neovascularization, Pathologic
Oxygen
Phosphorylation
Piperazines
Platelet Endothelial Cell Adhesion Molecule-1
Pressure
Pyrimidines
Random Allocation
Receptor, Platelet-Derived Growth Factor beta
Vascular Endothelial Growth Factor A
Xenograft Model Antitumor Assays
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https://hdl.handle.net/10161/16114Published Version (Please cite this version)
10.1038/sj.bjc.6603366Publication Info
Vlahovic, G; Rabbani, ZN; Herndon, JE; Dewhirst, MW; & Vujaskovic, Z (2006). Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta
and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation.
Br J Cancer, 95(8). pp. 1013-1019. 10.1038/sj.bjc.6603366. Retrieved from https://hdl.handle.net/10161/16114.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Mark Wesley Dewhirst
Gustavo S. Montana Distinguished Professor Emeritus of Radiation Oncology
Mark W. Dewhirst, DVM, PhD is the Gustavo S. Montana Professor of Radiation Oncology
and Vice Director for Basic Science in the Duke Cancer Institute. Dr. Dewhirst has
research interests in tumor hypoxia, angiogenesis, hyperthermia and drug transport.
He has spent 30 years studying causes of tumor hypoxia and the use of hyperthermia
to treat cancer. In collaboration with Professor David Needham in the Pratt School
of Engineering, he has developed a novel thermally sensitive drug carrying liposom
James Emmett Herndon II
Professor of Biostatistics & Bioinformatics
Current research interests have application to the design and analysis of cancer clinical
trials. Specifically, interests include the use of time-dependent covariables within
survival models, the design of phase II cancer clinical trials which minimize some
of the logistical problems associated with their conduct, and the analysis of longitudinal
studies with informative censoring (in particular, quality of life studies of patients
with advanced cancer).
Gordana Vlahovic
Adjunct Associate Professor in the Department of Medicine
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