title: 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.
authors.affiliation: Duke University Medical Center, P.O. Box 3335, Durham, NC 27710, USA. vlaho001@mc.duke.edu
authors.forename: G
authors.initials: G
authors.lastname: Vlahovic
authors.forename: Z N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: J E
authors.initials: JE
authors.lastname: Herndon
authors.forename: M W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Z
authors.initials: Z
authors.lastname: Vujaskovic
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D045604:Extracellular Fluid / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011312:Pressure; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D010100:Oxygen