Modifications in Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameters After α-Particle-Emitting 227Th-trastuzumab Therapy of HER2-Expressing Ovarian Cancer Xenografts

Purpose: The purpose of this study was to investigate the effect of alpha-particle-emitting Th-227-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of Th-227-trastuzumab. Methods and Materials: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 +/- 36 mm(3) (mean +/- SEM) were treated with a single injection of either Th-227-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of Th-227-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Results: Significant increases of kep, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and k(el), the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of k(ep) and theamplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). Conclusions: Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after Th-227-trastuzumab treatment of HER2-expressing ovarian cancer xenografts. (C) 2013 Elsevier Inc.