Abstract
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.
Footnotes
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J.-F.H.G. was supported by National Cancer Center Grant R01 CA100883-01 and the Abdulrahman Abdulmalik Research Fund.
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M.V., J.A.V., and M.B. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.141093.
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ABBREVIATIONS: 3-BrPA, 3-bromopyruvate; [14C]3-BrPA, 14C-labeled 3-BrPA; PBS, phosphate-buffered saline; FDG, 18F-deoxyglucose; PET, positron emission tomography; ID, injected dose; %ID/g, percentage of injected dose per gram of tissue.
- Received May 12, 2008.
- Accepted June 27, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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