Effect of O-4-ethoxyl-butyl-berbamine in combination with pegylated liposomal doxorubicin on advanced hepatoma in mice

• Published in: World journal of gastroenterology : WJG 2004-04, Vol.10 (7), p.950-953
• Main Authors: Fang, Bai-Jun, Yu, Mei-Li, Yang, Shao-Guang, Liao, Lian-Ming, Liu, Jie-Wen, Zhao, Robert C-H
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Benzylisoquinolines - pharmacology; Calmodulin - antagonists & inhibitors; Carcinoma, Hepatocellular - pathology; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacology; Drug Synergism; Liver Cancer; Liver Neoplasms - pathology; Mice; Mice, Inbred BALB C; O-4-乙氧基-丁基-小檗胺; 动物实验; 联合化疗; 肝细胞瘤; 药物毒性; 进展期; 阿霉素
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v10.i7.950

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 (2.5×10^6) 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 H22cells 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