• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Therapeutic Effect of Adenovirus- and alpha-fetoprotein Promoter-mediated tBid and Chemotherapeutic Agents in Combination on Orthotopic Hepatocellular Carcinoma in Mice.
【24h】

Therapeutic Effect of Adenovirus- and alpha-fetoprotein Promoter-mediated tBid and Chemotherapeutic Agents in Combination on Orthotopic Hepatocellular Carcinoma in Mice.

机译：腺病毒和甲胎蛋白启动子介导的tBid和化学治疗剂联合治疗对小鼠原位肝细胞癌的治疗作用。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Hepatocellular carcinoma (HCC) is the third commonest cancer worldwide. However HCC is considered to be highly resistant to chemotherapy. Gene therapies aimed to regulate Bd-2 proteins may sensitize HCC cells to chemotherapy. Studies have demonstrated that Bid/tBid are crucial in hepatocyte apoptosis. Bid also plays important roles in the development and chemotherapeutic sensitivity of HCC. The objective of this study is to test effect of Ad/AFPtBid and chemotherapeutic agents in combination on an orthotopic HCC model.;The mice bearing orthotopic HCC tumors were treated with Ad/AFPtBid alone or in combination with 5-FU/Dox. Serum AFP levels were measured to mornitor tumor progression. The mice were killed four weeks after treatment. Liver tissues were subjected to immunohistochemical staining of proliferation cell nuclear antigen (PCNA) and TUNEL staining. Another batch of mice was observed for survival rate over a six month period. In addition, possible side effects of Ad/AFPtBid were tested in BALB/c mice. Results demonstrated that Ad/AFPtBid significantly inhibited Hep3B tumor growth. The combination of Ad/AFPtBid with 5-FU was more effective in tumor regression than either agent alone. However, the combination of Ad/AFPtBid with Dox treatment failed to demonstrated better effect than Dox treatment alone because the mice that received Dox exhibited serious weight loss. Tumor tissues from Ad/AFPtBid alone or combination treatment groups showed a decrease in cells positive for PCNA, and an increase in apoptosis by TUNEL staining, indicating that Ad/AFPtBid induced tumor regression through its pro-apoptotic effect. Inflammatory cell infiltration was also increased. Furthermore, Ad/AFPtBid did not suppress the hepatic tumor formed by non-AFP producing SK-HEP-1 or DLD-1. Finally, Ad/AFPtBid and 5-FU in combination results in better survival rate. No acute toxic effect of Ad/AFPtBid was observed.;It is well established that many apoptosis inducers act in a cell cycle-specific fashion. This leads us to hypothesize that tBid might have phase specific effect. So, we tested the susceptibility of Hep3B cells at 00/01, S or G2/M phases to tBid. The results revealed that tBid significantly reduced Hep3B cells in G0/G1 phase, increased cells in G2/M phase. On the contrary, 5-FU arrested Hep3B cells in G0/G1 phase, and significantly reduced cells in G2/M phase. The levels of cell cycle-related proteins were altered in line with the result of the cell cycle. This suggests Hep3B cells in G0/G1 phase may be more susceptible to tBid. The complementary effects tBid and 5-FU on different phases of the cell cycle may explain the better therapeutic result if both are used to treat HCC.;In conclusion, (1) Ad/AFPtBid can specifically target and effectively suppress the AFP-producing HCC. (2) Ad/AFPtBid can significantly sensitize HCC to 5-FU, their combination can significantly increase the anti-tumor effectiveness. (3) Ad/AFPtBid shows little toxicity in vivo. (4) The complementary effect of tBid and 5-FU on different phases of the cell cycle may explain the better therapeutic result if both are used to treat HCC. (5) The elucidation of phase specific effect of tBid points to a possible therapeutic option that combines tBid with different phase specific agents to treat HCC.
机译：肝细胞癌（HCC）是全球第三大常见癌症。但是，HCC被认为对化疗具有高度抵抗力。旨在调节Bd-2蛋白的基因疗法可能会使HCC细胞对化疗敏感。研究表明，Bid / tBid在肝细胞凋亡中至关重要。投标在肝癌的发展和化学治疗敏感性中也起着重要作用。这项研究的目的是测试Ad / AFPtBid和化学治疗剂联合对原位HCC模型的作用。单独或与5-FU / Dox联合使用Ad / AFPtBid治疗患有原位HCC肿瘤的小鼠。测量血清AFP水平以监测肿瘤进展。治疗后四周将小鼠处死。对肝组织进行增殖细胞核抗原（PCNA）的免疫组织化学染色和TUNEL染色。观察到另一批小鼠在六个月内的存活率。另外，在BALB / c小鼠中测试了Ad / AFPtBid的可能的副作用。结果表明，Ad / AFPtBid显着抑制了Hep3B肿瘤的生长。 Ad / AFPtBid与5-FU的结合比单独使用任何一种药物更有效。但是，Ad / AFPtBid与Dox治疗的结合未能显示出比单独Dox治疗更好的效果，因为接受Dox的小鼠表现出严重的体重减轻。 Ad / AFPtBid单独或联合治疗组的肿瘤组织显示PCNA阳性细胞减少，TUNEL染色显示凋亡增加，表明Ad / AFPtBid通过促凋亡作用诱导肿瘤消退。炎性细胞浸润也增加。此外，Ad / AFPtBid不能抑制由非AFP产生的SK-HEP-1或DLD-1形成的肝肿瘤。最后，Ad / AFPtBid和5-FU结合使用可提高生存率。没有观察到Ad / AFPtBid的急性毒性作用。众所周知，许多凋亡诱导剂以细胞周期特异性方式起作用。这使我们假设tBid可能具有特定阶段的效果。因此，我们测试了00/01，S或G2 / M期Hep3B细胞对tBid的敏感性。结果表明，tBid显着减少了G0 / G1期的Hep3B细胞，增加了G2 / M期的Hep3B细胞。相反，5-FU使Hep3B细胞停滞在G0 / G1期，并显着减少了G2 / M期的细胞。细胞周期相关蛋白的水平随细胞周期的变化而变化。这表明处于G0 / G1期的Hep3B细胞可能对tBid更敏感。如果同时使用tBid和5-FU在细胞周期的不同阶段的互补作用可以解释更好的治疗结果。结论：（1）Ad / AFPtBid可以特异性靶向并有效抑制产生AFP的HCC 。 （2）Ad / AFPtBid可以使HCC对5-FU明显敏感，将其联合使用可以显着提高抗肿瘤效果。 （3）Ad / AFPtBid在体内几乎没有毒性。 （4）如果同时使用tBid和5-FU对HCC的互补作用，可以解释更好的治疗效果。 （5）tBid的阶段特异性作用的阐明指出了将tBid与不同的阶段特异性药物联合治疗HCC的可能的治疗选择。

著录项

  • 作者

    Ma, Shihong.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Biology Cell.;Health Sciences Medicine and Surgery.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 138 p.
  • 总页数 138
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号