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Early Therapy Evaluation of Combined Anti–Death Receptor 5 Antibody and Gemcitabine in Orthotopic Pancreatic Tumor Xenografts by Diffusion-Weighted Magnetic Resonance Imaging

Departments of ¹ Radiology, ² Biomedical Engineering, ³ Radiation Oncology, ⁴ Medicine, ⁵ Pathology, and ⁶ Surgery, and ⁷ Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Hyunki Kim, BDB 815, University of Alabama at Birmingham, Birmingham, AL 35294-0012. E-mail: Hyunki{at}uab.edu or Kurt R. Zinn, BDB 802, University of Alabama at Birmingham, Birmingham, AL 35294-0012. Phone: 205-975-6414; Fax: 205-975-6522; E-mail: Kurtzinn{at}uab.edu.

Key Words: death receptor 5 • TRA-8 • pancreatic cancer • DWI • apoptosis

Early therapeutic efficacy of anti–death receptor 5 antibody (TRA-8) combined with gemcitabine was measured using diffusion-weighted magnetic resonance imaging (DWI) in an orthotopic pancreatic tumor model. Groups 1 to 4 of severe combined immunodeficient mice (n = 5–7 per group) bearing orthotopically implanted, luciferase-positive human pancreatic tumors (MIA PaCa-2) were subsequently (4–5 weeks thereafter) injected with saline (control), gemcitabine (120 mg/kg), TRA-8 (200 µg), or TRA-8 combined with gemcitabine, respectively, on day 0. DWI, anatomic magnetic resonance imaging, and bioluminescence imaging were done on days 0, 1, 2, and 3 after treatment. Three tumors from each group were collected randomly on day 3 after imaging, and terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling staining was done to quantify apoptotic cellularity. At just 1 day after starting therapy, the changes of apparent diffusion coefficient (ADC) in tumor regions for group 3 (TRA-8) and group 4 (TRA-8/Gem) were 21 ± 9% (mean ± SE) and 27 ± 3%, respectively, significantly higher (P < 0.05) than those of group 1 (–1 ± 5%) and group 2 (–2 ± 4%). There was no statistical difference in tumor volumes for the groups at this time. The mean ADC values of groups 2 to 4 gradually increased over 3 days, which were concurrent with tumor volume regressions and bioluminescence signal decreases. Apoptotic cell densities of tumors in groups 1 to 4 were 0.7 ± 0.4%, 0.6 ± 0.2%, 3.1 ± 0.9%, and 4.7 ± 1.0%, respectively, linearly proportional to the ADC changes on day 1. Further, the ADC changes were highly correlated with the previously reported mean survival times of animals treated with the same agents and doses. This study supports the clinical use of DWI for pancreatic tumor patients for early assessment of drug efficacy. [Cancer Res 2008;68(20):8369–76]