Liver Cancer
Copyright ©The Author(s) 2004. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 1, 2004; 10(7): 950-953
Published online Apr 1, 2004. doi: 10.3748/wjg.v10.i7.950
Effect of O-4-ethoxyl-butyl-berbamine in combination with pegylated liposomal doxorubicin on advanced hepatoma in mice
Bai-Jun Fang, Mei-Li Yu, Shao-Guang Yang, Lian-Ming Liao, Jie-Wen Liu, Robert -C-H Zhao
Bai-Jun Fang, Mei-Li Yu, Shao-Guang Yang, Lian-Ming Liao, Jie-Wen Liu, Robert -C-H Zhao, Sino-American Collaborative Laboratory, Stat Key Laboratory of Experimental Haematology, Institute of Haematology and Blood Disease Hospital, and Tissue Engineering Center, Chinese Academy of Medical Sciences, Tianjin 300020, China
Author contributions: All authors contributed equally to the work.
Supported by Tianjin Natural Foundation of Sciences, No. 941409017 and the Minister of Public Health of China, No. 94-2-024
Correspondence to: Robert Chun-Hua Zhao, Professor of State Key Laboratory of Experimental Haematology. Institute of Hematology and Blood Disease Hospital, and Tissue Engineering Center, Chinese Academy of Medical Sciences, Tianjin 300020, China. chunhuaz@public.tpt.tj.cn
Telephone: +86-22-27210060 Fax: +86-22-27210060
Received: May 12, 2003
Revised: May 25, 2003
Accepted: June 27, 2003
Published online: April 1, 2004
Abstract

AIM: To study the synergistic effects of calmodulin (CaM) antagonist O-4-ethoxyl-butyl-berbamine (EBB) and pegylated liposomal doxorubicin (PLD) on hepatoma-22 (H22) in vivo.

METHODS: Hepatoma model was established in 50 Balb/c mice by inoculating H22 cells (2.5 × 106) subcutaneously into the right backs of the mice. These mice were divided into 5 groups, and treated with saline only, PLD only, doxorubicin (Dox) only, PLD plus EBB and Dox plus EBB, respectively. In the treatment groups, mice were given 5 intravenous of PLD or Dox on days 0, 3, 6, 9 and 12. The first dosage of PLD or Dox was 4.5 mg/kg, the other 4 injections was 1 mg/kg. EBB (5 mg/kg) was coadministered with PLD or Dox in the corresponding groups. The effect of drugs on the life spans of hepatoma-bearing mice and tumor response to the drugs were recorded. Dox levels in the hepatoma cells were measured by a fluorescence assay. Light microscopy was performed to determine the histopathological changes in the major organs of these tumor-bearing mice. The MTT method was used to analyze the effect of Dox or PLD alone, Dox in combination with EBB, or PLD in combination with EBB on the growth of H22 cells in an in vitro experiment.

RESULTS: EBB (5 mg/kg) significantly augmented the antitumor activity of Dox or PLD, remarkably prolonged the median survival time. The median survival time was 18.2 d for control group, but 89.2 d for PLD + EBB group and 70.1 d for Dox + EBB group, respectively. However, Dox alone did not show any remarkable antitumor activity, and the median survival time was just 29.7 d. Addition of EBB to Dox or PLD significantly increased the level of Dox in H22 cells in vivo. Moreover, EBB diminished liver toxicity of Dox and PLD. In vitro, EBB reduced the IC50 value of Dox or PLD on H22 cells from 0.050 ± 0.006 mg/L and 0.054 ± 0.004 mg/L to 0.012 ± 0.002 mg/L and 0.013 ± 0.002 mg/L, respectively (P < 0.01).

CONCLUSION: EBB and liposomization could improve the therapeutic efficacy of Dox in liver cancer, while decreasing its liver toxicity.

Keywords: $[Keywords]