Fang Bai-Jun, Yu Mei-Li, Yang Shao-Guang, Liao Lian-Ming, Liu Jie-Wen, Zhao Robert C-H
State Key Laboratory of Experimental Haematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, Tianjin 300020, China.
World J Gastroenterol. 2004 Apr 1;10(7):950-3. doi: 10.3748/wjg.v10.i7.950.
To study the synergistic effects of calmodulin (CaM) antagonist O-4-ethoxyl-butyl-berbamine (EBB) and pegylated liposomal doxorubicin (PLD) on hepatoma-22 (H(22)) in vivo.
Hepatoma model was established in 50 Balb/c mice by inoculating H(22) cells (2.5 x 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 H(22) cells in an in vitro experiment.
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 H(22) cells in vivo. Moreover, EBB diminished liver toxicity of Dox and PLD. In vitro, EBB reduced the IC50 value of Dox or PLD on H(22) 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).
EBB and liposomization could improve the therapeutic efficacy of Dox in liver cancer, while decreasing its liver toxicity.
研究钙调蛋白（CaM）拮抗剂O-4-乙氧基丁基小檗胺（EBB）与聚乙二醇化脂质体阿霉素（PLD）对肝癌-22（H(22)）的体内协同作用。
将50只Balb/c小鼠右侧背部皮下接种H(22)细胞（2.5×10(6)）建立肝癌模型。将这些小鼠分为5组，分别给予生理盐水、单纯PLD、单纯阿霉素（Dox）、PLD加EBB和Dox加EBB处理。在治疗组中，小鼠于第0、3、6、9和12天静脉注射5次PLD或Dox。PLD或Dox的首次剂量为4.5mg/kg，其余4次注射为1mg/kg。EBB（5mg/kg）与PLD或Dox在相应组中联合给药。记录药物对荷瘤小鼠寿命的影响以及肿瘤对药物的反应。通过荧光测定法测量肝癌细胞中的Dox水平。进行光学显微镜检查以确定这些荷瘤小鼠主要器官的组织病理学变化。在体外实验中，采用MTT法分析单独的Dox或PLD、Dox与EBB联合、或PLD与EBB联合对H(22)细胞生长的影响。
EBB（5mg/kg）显著增强了Dox或PLD的抗肿瘤活性，显著延长了中位生存时间。对照组的中位生存时间为18.2天，而PLD+EBB组为89.2天，Dox+EBB组为70.1天。然而，单独的Dox未显示出任何显著的抗肿瘤活性，中位生存时间仅为29.7天。在Dox或PLD中加入EBB显著提高了体内H(22)细胞中Dox的水平。此外，EBB降低了Dox和PLD的肝毒性。在体外，EBB将Dox或PLD对H(22)细胞的IC50值分别从0.050±0.006mg/L和0.054±0.004mg/L降低至0.012±0.002mg/L和0.013±0.002mg/L（P<0.01）。
EBB和脂质体化可提高Dox在肝癌治疗中的疗效，同时降低其肝毒性。
