AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging

• Published in: Magnetic resonance imaging 2007-04, Vol.25 (3), p.319-327
• Main Authors: Wilmes, Lisa J, Pallavicini, Maria G, Fleming, Lisa M, Gibbs, Jessica, Wang, Donghui, Li, Ka-Loh, Partridge, Savannah C, Henry, Roland G, Shalinsky, David R, Hu-Lowe, Dana, Park, John W, McShane, Teresa M, Lu, Ying, Brasch, Robert C, Hylton, Nola M
• Format: Article
• Language: English
• Subjects: Animals; Anti-angiogenic; Antineoplastic Agents - administration & dosage; Breast cancer; Breast Neoplasms - blood supply; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Capillary Permeability - drug effects; Cell Proliferation - drug effects; Contrast Media; Dynamic contrast-enhanced MRI (DCE-MRI); Female; Imidazoles - therapeutic use; Indazoles - therapeutic use; Magnetic Resonance Imaging - methods; Mice; Mice, Nude; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - prevention & control; Radiology; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; src-Family Kinases - antagonists & inhibitors; Treatment Outcome; Vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor
• ISSN: 0730-725X; 1873-5894
• DOI: 10.1016/j.mri.2006.09.041

Abstract Dynamic contrast-enhanced MRI (DCE-MRI) was used to noninvasively evaluate the effects of AG-03736, a novel inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, on tumor microvasculature in a breast cancer model. First, a dose response study was undertaken to determine the responsiveness of the BT474 human breast cancer xenograft to AG-013736. Then, DCE-MRI was used to study the effects of a 7-day treatment regimen on tumor growth and microvasculature. Two DCE-MRI protocols were evaluated: (1) a high molecular weight (MW) contrast agent (albumin-(GdDTPA)30 ) with pharmacokinetic analysis of the contrast uptake curve and (2) a low MW contrast agent (GdDTPA) with a clinically utilized empirical parametric analysis of the contrast uptake curve, the signal enhancement ratio (SER). AG-013736 significantly inhibited growth of breast tumors in vivo at all doses studied (10–100 mg/kg) and disrupted tumor microvasculature as assessed by DCE-MRI. Tumor endothelial transfer constant ( Kps ) measured with albumin-(GdDTPA)30 decreased from 0.034±0.005 to 0.003±0.001 ml min−1 100 ml−1 tissue ( P