title: Detection of early antiangiogenic effects in human colon adenocarcinoma xenografts: in vivo changes of tumor blood volume in response to experimental VEGFR tyrosine kinase inhibitor.
abstract: Antiangiogenesis is emerging as efficient strategy for targeting and potentially eliminating neoplastic tumor vessels. The main goal of this study was to establish whether absolute tumor blood volume (V(b)) change could be used as an early predictor of antiangiogenesis in ectopic and orthotopic colon carcinomas. To assess therapy-induced changes of V(b), we did comparative analysis of signal intensities in tumors and muscle using steady-state magnetic resonance imaging (MRI) assisted with an intravascular paramagnetic contrast agent [gadolinium-labeled protected graft copolymer (PGC-Gd)]. Athymic mice with implanted human MV522 tumors were treated with vascular endothelial growth factor type 2 receptor tyrosine kinase inhibitor (VEGFR2-TKI) that has been shown to inhibit VEGFR2 phosphorylation and tumor growth in vivo. Animals were imaged either after a single day or after a 1-week course of treatments. The measured V(b) in ectopic tumors was 2.5 +/- 1.5% of total tissue volume 1 week after the implantation (n = 8). Two doses of VEGFR2-TKI (25 mg/kg, p.o., b.i.d.) resulted in a decrease of V(b) to 1.3 +/- 0.3%. In orthotopic tumors, the measured V(b) was initially higher (11.9 +/- 2.0%); however, VEGFR2-TKI treatment also resulted in a statistically significant decrease of V(b). The absolute V(b) was not affected in the muscle as a result of treatments. MRI measurements were corroborated by using isotope and correlative histology experiments. Our results show that steady-state MRI is highly sensitive to early antiangiogenic effects caused by small molecule drugs.
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital, Charlestown, MA 01655, USA.
authors.forename: Young Ro
authors.initials: YR
authors.lastname: Kim
authors.forename: Anna
authors.initials: A
authors.lastname: Yudina
authors.forename: Joseluis
authors.initials: J
authors.lastname: Figueiredo
authors.forename: Wilfried
authors.initials: W
authors.lastname: Reichardt
authors.forename: Dana
authors.initials: D
authors.lastname: Hu-Lowe
authors.forename: Alexander
authors.initials: A
authors.lastname: Petrovsky
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Kang
authors.forename: Denise
authors.initials: D
authors.lastname: Torres
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Bogdanov
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000098:blood supply*; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000097:blood / Q000098:blood supply*; D004911:Erythrocyte Volume; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D018810:Magnetic Resonance Angiography; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011877:Radionuclide Imaging; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C508051:AG 013925; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2