Intraarterial therapy with a new potent inhibitor of tumor metabolism (3-bromopyruvate): identification of therapeutic dose and method of injection in an animal model of liver cancer

J Vasc Interv Radiol. 2007 Jan;18(1 Pt 1):95-101. doi: 10.1016/j.jvir.2006.10.019.

Abstract

Purpose: A potent new adenosine triphosphate inhibitor--3-bromopyruvate (3-BrPA)--has been shown to have antitumor effects when injected intraarterially in the hepatic artery of rabbits with VX-2 tumors. The authors performed a stepwise study in rabbits to determine the therapeutic dose and method of delivery of 3-BrPA.

Materials and methods: White New Zealand rabbits with VX-2 tumors were used for this study. Eight animals were examined to establish the maximum tolerated dose (2.5 or 5.0 mmol/L of 25-mL 3-BrPA) as a single bolus injection. The 2.5 mmol/L dose was then used to compare three methods of delivery: injection of one bolus, two 12.5-mL serial bolus injections administered 1 hour apart, and continuous infusion of 25 mL for 1 hour. Finally, dose-response analysis was performed by using 10 groups of three animals each, with 1-hour intraarterial infusions of 3-BrPA (25 mL) at incremental doses of 0.25 mmol/L (range, 0.5-2.5 mmol/L) with phosphate buffered saline used for control animals. All animals were sacrificed at 48 hours, and histopathologic analysis was performed. chi2 statistics were used to analyze the data.

Results: The maximum tolerated dose of 3-BrPA was 2.5 mmol/L; however, it caused substantial peripheral liver necrosis. These effects were minimized when 3-BrPA was infused over 1 hour. Complete tumor necrosis was identified in all samples with at least 2.0 mmol/L of 3-BrPA. The 1.75 mmol/L concentration was identified as therapeutic because it caused complete tumor apoptosis and minimal toxicity (P < .001).

Conclusions: The results identified both the therapeutic dose (1.75 mmol/L) and the method of infusion (1 hour intraarterial infusion) of 3-BrPA. This potent new treatment may prove to be an effective way of treating liver cancer and may become part of a new class of anticancer drugs based on the inhibition of tumor metabolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Catheterization
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / adverse effects
  • Hepatic Artery
  • Infusions, Intra-Arterial
  • Injections, Intra-Arterial
  • Liver Neoplasms, Experimental / drug therapy*
  • Liver Neoplasms, Experimental / metabolism
  • Maximum Tolerated Dose
  • Pyruvate Dehydrogenase Complex / antagonists & inhibitors*
  • Pyruvates / administration & dosage*
  • Pyruvates / adverse effects
  • Rabbits

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Pyruvate Dehydrogenase Complex
  • Pyruvates
  • bromopyruvate