Novel Intraarterial Therapy for Liver Cancer Using Ethylbromopyruvate Dissolved in an Iodized Oil

Abstract

Rationale and Objectives: In spite of various therapies developed, hepatocellular carcinoma still shows poor prognosis. In this study, we introduced ethylbromopyruvate (EBrP), a hydrophobic derivative of 3-bromopyruvate, as an agent for intraarterial therapy of hepatocellular carcinoma. Materials and Methods: In in vitro study, we evaluated whether EBrP induced apoptotic cell death in Huh-BAT cells. Chemical degradation products of EBrP were identified by performing proton nuclear magnetic resonance spectroscopy and thin layer chromatography. VX2 carcinoma was implanted and grown in the liver of 25 rabbits for in vivo study. By transfemoral intraarterial approach, 0.4 mL of 10 mM and 40 mM EBrP dissolved in an iodized oil (Lipiodol) was infused into the proper hepatic artery in 8 and 10 rabbits, respectively. In the remaining seven rabbits, 0.4 mL of Lipiodol alone was intraarterially injected as a control. One week later, tumor necrosis rate was calculated with histopathologic examination and hepatotoxicity was evaluated with biochemical analysis. Results: EBrP induced apoptosis in human HCC cells via mitochondrial apoptotic signaling cascades. EBrP dissociated into 3-bromopyruvate and ethanol in the aqueous environment. In VX2 liver tumor models, the group of intraarterial delivery of 40 mM EBrP/Lipiodol solution showed higher tumor necrosis rates (96.1% +/- 3.8) than the other groups (38.9% +/- 15.9 of a control, 90.5% +/- 2.9 in 10 mM) (P < .05). There was transient elevation of AST and ALT enzyme levels without any mortality. Conclusions: Intraarterial infusion of EBrP/Lipiodol solution is a feasible intraarterial therapy for liver tumors with potent antitumor effects and transient hepatotoxicity.