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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

Center for Molecular Imaging Research, Massachusetts General Hospital, Charlestown, Massachusetts

Requests for reprints: Alexei A. Bogdanov, Jr., Department of Radiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Phone: 508-856-5571; Fax: 508-856-1860; E-mail: Alexei.Bogdanov{at}umassmed.edu.

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.

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