Korean J Radiol.  2009 Dec;10(6):596-603. 10.3348/kjr.2009.10.6.596.

The Antitumor Effect and Hepatotoxicity of a Hexokinase II Inhibitor 3-Bromopyruvate: In Vivo Investigation of Intraarterial Administration in a Rabbit VX2 Hepatoma Model

• Jae HJ
• Chung JW
• Park HS
• Lee MJ
• Lee KC
• Kim HC
• Yoon JH
• Chung H
• Park JH

• KMID: 1102563
• DOI: http://doi.org/10.3348/kjr.2009.10.6.596

Abstract

OBJECTIVE
The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. MATERIALS AND METHODS: This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3-BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/ 0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. RESULTS: The tumor necrosis rate was significantly higher in the high dose group (93% +/- 7.6 [mean +/- SD]) than that in the control group (48% +/- 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% +/- 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% +/- 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. CONCLUSION: Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method.

Keyword

Hepatocellular carcinoma; 3-Bromopyruvate; Hexokinase II inhibitor; Intraarterial chemotherapy; VX2 carcinoma

MeSH Terms

Animals
Disease Models, Animal
Dose-Response Relationship, Drug
Doxorubicin/administration & dosage/pharmacology
Infusions, Intra-Arterial
Iodized Oil/administration & dosage/pharmacology
Liver Neoplasms, Experimental/*drug therapy/radiography
Pyruvates/administration & dosage/*pharmacology
Rabbits
Statistics, Nonparametric
Tomography, X-Ray Computed

Figure

• 

  Fig. 1 Tumor necrosis rates (%) of experimental groups (expressed as mean tumor necrosis rate ± SD). Tumor necrosis rate was significantly higher in high dose group (93% ± 7.6) than that in control group (48% ± 21.7) (p = 0.0002), but tumor necrosis rate was not significantly higher in low dose group (62% ± 20.0) (p = 0.2780). However, tumor necrosis rate of high dose group was significantly lower than that of Lipiodol-doxorubicin treatment group (99% ± 2.7) (p = 0.0015).

• 

  Fig. 2 Representative case of 3-BrPA 1 mM group.A. Contrast-enhanced CT image obtained one day before intraarterial administration shows low attenuated VX2 carcinoma in left hepatic lobe of rabbit (arrow).B. On selective left hepatic angiography that was done just before transcatheter intraarterial administration, hypervascular tumor staining is seen in left hepatic lobe (arrows). After microcatheter was advanced to left hepatic artery, low dose 3-BrPA solution (25 mL in 1 mM concentration) was infused for 2 minutes.C. Photograph of resected specimen of tumor. Pathologic specimens containing tumor were sectioned in same transverse plane that was used for CT scan with 5-mm intervals, and slice with largest tumor area was embedded in paraffin for histologic examination.D. Photomicroscopic slide of same specimen (Hematoxylin & Eosin staining, ×1). Necrosis rate of tumor is 81%.

• 

  Fig. 3 Representative case of 3-BrPA 5 mM group.A. Contrast-enhanced CT image obtained one day before intraarterial administration shows low attenuated mass with enhancing rim in left hepatic lobe (arrow).B. On selective hepatic arteriography, hypervascular tumor staining is seen in left hepatic lobe (arrows).C. Photograph of resected specimen of tumor.D. Photomicroscopic slide of same specimen (Hematoxylin & Eosin staining, ×1). Necrosis rate of tumor is 99%.

• 

  Fig. 4 Biochemical analysis of liver enzymes; mean values of liver enzymes in each group. Line graph shows that aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels tended to transiently increase at one day after intraarterial administration and they decreased to levels close to normal at seven days. Levels of AST and ALT of high dose 3-BrPA group and Lipiodol-doxorubicin emulsion group were significantly elevated as compared to those levels of control group at one day, whereas those levels of low dose 3-BrPA group did not show statistically significant difference as compared with those levels of control group. There was also no significant difference between both AST and ALT enzyme levels of high dose 3-BrPA group and those of Lipiodol-doxorubicin emulsion group.A. AST levels.B. ALT levels.

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