title: Examining the acute effects of cediranib (RECENTIN, AZD2171) treatment in tumor models: a dynamic contrast-enhanced MRI study using gadopentate.
abstract: Cediranib (RECENTIN, AZD2171) is a highly potent inhibitor of the tyrosine kinase activity associated with all three vascular endothelial growth factor (VEGF) receptors and is currently in Phase II/III clinical trials. Preclinically, cediranib inhibits VEGF signaling and angiogenesis in vivo and impedes solid tumor growth significantly. Clinically, changes observed using dynamic contrast-enhanced MRI (DCE-MRI) with gadopentate suggest that acute cediranib treatment compromises tumor hemodynamics. In this study, a DCE-MRI baseline scan using gadopentate was performed in nude rats bearing Lovo (human colorectal carcinoma) or C6 (rat glioma) tumors. Cediranib (3 mg/kg per day) or vehicle was then dosed orally (2, 26 and 50 h after the baseline scan; 12 rats per group) and a second scan acquired 2 h after the final dosing event. Mean values for K(trans) (Tofts and Kermode-derived) [Magn Reson Med 17 (1991) 357-67] and the initial area under the gadolinium concentration curve over the first 60 s (iAUC) were reduced significantly following cediranib treatment: K(trans) by 33% (P<.05) in both tumor models and iAUC by 23% (P>.05) and 33% (P>.005) in Lovo and C6, respectively. This is the first preclinical investigation to examine the effect of cediranib treatment on tumors by DCE-MRI with gadopentate.
authors.affiliation: Department of Enabling Capabilities and Sciences, AstraZeneca, Mereside, Alderley Park, Cheshire, SK10 4TG, UK.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Bradley
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Tessier
authors.forename: Tony
authors.initials: T
authors.lastname: Lacey
authors.forename: Marietta
authors.initials: M
authors.lastname: Scott
authors.forename: Juliane M
authors.initials: JM
authors.lastname: Jürgensmeier
authors.forename: Rajesh
authors.initials: R
authors.lastname: Odedra
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mills
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Kilburn
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D003287:Contrast Media; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019786:Gadolinium DTPA; D005910:Glioma / Q000175:diagnosis* / Q000188:drug therapy*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D011799:Quinazolines / Q000008:administration & dosage*; D051381:Rats; D011923:Rats, Nude; D016896:Treatment Outcome; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D019786:Gadolinium DTPA; D011799:Quinazolines; C500926:cediranib; D007211:Indoles