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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Targeting of VX2 Rabbit Liver Tumor by Selective Delivery of 3-Bromopyruvate: A Biodistribution and Survival Study

Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, Maryland

The aim of this study was to determine the biodistribution and tumor targeting ability of ¹⁴C-labeled 3-bromopyruvate ([¹⁴C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [¹⁴C]3-BrPA on tumor and healthy tissue glucose metabolism by determining ¹⁸F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM [¹⁴C]3-BrPA i.a., 1.75 mM [¹⁴C]3-BrPA i.v., 20 mM [¹⁴C]3-BrPA i.v., or 25 ml of phosphate-buffered saline (PBS). All rabbits (with the exception of the 20 mM i.v. group) received FDG 1 h before sacrifice. Next, we compared survival of animals treated with i.a. administered 1.75 mM [¹⁴C]3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of [¹⁴C]3-BrPA was 1.8 ± 0.2% percentage of injected dose per gram of tissue (%ID/g), whereas other tissues showed minimal uptake. After i.v. infusion (1.75 mM), tumor uptake of [¹⁴C]3-BrPA was 0.03 ± 0.01% ID/g. After i.a. administration of [¹⁴C]3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of [¹⁴C]3-BrPA, there was no significant difference in tumor FDG uptake. Survival analysis showed that rabbits treated with 1.75 mM 3-BrPA survived longer (55 days) than controls (18.6 days). Intra-arterially delivered 3-BrPA has a favorable biodistribution profile, combining a high tumor uptake resulting in blockage of FDG uptake with no effects on healthy tissue. The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit.

Address correspondence to: Dr. Jean-Francois H. Geschwind, Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Vascular and Interventional Radiology, 600 North Wolfe St., Blalock 545, Baltimore, MD 21287. E-mail: jfg{at}jhmi.edu