title: Preclinical evaluation of tumor microvascular response to a novel antiangiogenic/antitumor agent RO0281501 by dynamic contrast-enhanced MRI at 1.5 T.
abstract: Inhibition of tumor angiogenesis is a promising approach in cancer treatment. The purpose of this study was to evaluate the vascular response of human lung tumor xenografts in vivo to RO0281501, an inhibitor of tyrosine kinase receptors, including vascular endothelial growth factor receptor 2, fibroblast growth factor receptor, and platelet-derived growth factor receptor, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Human non-small cell lung carcinoma (H460a) xenografts grown s.c. in athymic nu/nu mice were treated p.o. with the antiangiogenic agent RO0281501. Treatment-induced changes in tumor volume, epiphyseal growth plate thickness, and microvessel density assessed by CD31 immunohistochemistry were analyzed. Tumor vascular permeability and perfusion were measured in tumors using DCE-MRI with gadopentetate dimeglumine on a 1.5 T clinical scanner to assess vascular function. Treatment with RO0281501 resulted in significant growth retardation of H460a tumors. RO0281501-treated tumors showed histologic evidence of growth plate thickening and relatively lower microvessel density compared with the controls. Regarding DCE-MRI variables, the initial slope of contrast uptake and Ak(ep) were significantly decreased on day 7 of treatment. RO0281501 is a novel antiangiogenic/antitumor agent, which is active in the H460a xenograft model. Its effects on tumor vasculature can be monitored and assessed by DCE-MRI on a 1.5 T human MR scanner with clinically available gadopentetate dimeglumine contrast, which will facilitate clinical trials with this or similar agents.
authors.affiliation: Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Manickam
authors.initials: M
authors.lastname: Muruganandham
authors.forename: Mihaela
authors.initials: M
authors.lastname: Lupu
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Dyke
authors.forename: Cornelia
authors.initials: C
authors.lastname: Matei
authors.forename: Michael
authors.initials: M
authors.lastname: Linn
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Jason A
authors.initials: JA
authors.lastname: Koutcher
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D003287:Contrast Media; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D019786:Gadolinium DTPA; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C515160:RO0281501; D001569:Benzodiazepines; D019786:Gadolinium DTPA