Targeting of VX2 rabbit liver tumor by selective delivery of 3-bromopyruvate: a biodistribution and survival study

J Pharmacol Exp Ther. 2008 Oct;327(1):32-7. doi: 10.1124/jpet.108.141093. Epub 2008 Jun 30.

Abstract

The aim of this study was to determine the biodistribution and tumor targeting ability of (14)C-labeled 3-bromopyruvate ([(14)C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [(14)C]3-BrPA on tumor and healthy tissue glucose metabolism by determining (18)F-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 [(14)C]3-BrPA i.a., 1.75 mM [(14)C]3-BrPA i.v., 20 mM [(14)C]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 [(14)C]3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of [(14)C]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 [(14)C]3-BrPA was 0.03 +/- 0.01% ID/g. After i.a. administration of [(14)C]3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of [(14)C]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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Radioisotopes
  • Fluorodeoxyglucose F18
  • Infusions, Intra-Arterial*
  • Liver Neoplasms, Experimental / drug therapy*
  • Liver Neoplasms, Experimental / mortality
  • Pyruvates / administration & dosage*
  • Pyruvates / pharmacokinetics*
  • Rabbits
  • Tissue Distribution

Substances

  • Carbon Radioisotopes
  • Pyruvates
  • Fluorodeoxyglucose F18
  • bromopyruvate