Novel intraarterial therapy for liver cancer using ethylbromopyruvate dissolved in an iodized oil.
OBJECTIVE
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.


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.
Department of Radiology, Seoul National University Boramae Hospital, Dongjak-gu, Seoul, Korea.
Young Ho
YH
Choi
Jin Wook
JW
Chung
Kyu Ri
KR
Son
Young Ho
YH
So
Won
W
Kim
Chang Jin
CJ
Yoon
Jung Hwan
JH
Yoon
Hesson
H
Chung
Hyo-Cheol
HC
Kim
Hwan Jun
HJ
Jae
Young Il
YI
Kim
Jae Hyung
JH
Park
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D004621:Embolization, Therapeutic / Q000379:methods*; D006490:Hemostatics / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007269:Injections, Intra-Arterial; D007459:Iodized Oil / Q000737:chemistry*; D008113:Liver Neoplasms / Q000628:therapy*; D011773:Pyruvates / Q000737:chemistry* / Q000627:therapeutic use*; D011817:Rabbits; D016896:Treatment Outcome
D004337:Drug Carriers; D006490:Hemostatics; D011773:Pyruvates; C017092:bromopyruvate; D007459:Iodized Oil