Oncolytic adenovirus driven by hypoxia- inducible Met promoter for the treatment of hepatocellular carcinoma

• Main Authors: Hao-Tien Wang, 王皓恬
• Other Authors: Chao-Liang Wu
• Format: Others
• Language: en_US
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/27806092724080838195

碩士 === 國立成功大學 === 生物化學研究所 === 93 === 　Hepatocellular carcinoma (HCC) is one of the most human malignant tumors in Taiwan. As this disease has a poor prognosis, an effective therapeutic modality is urgently needed. Replication-selective adenovirus has been reported to kill tumor cells and therefore can be one of the promising therapeutic approaches for cancer. Since hypoxia is a common characteristic of human tumors, which adversely affects the prognosis of cancer patients, targeting hypoxic regions may increase the effectiveness of cancer treatment. It is the reason why many researches have exploited hypoxia response element (HRE) to control gene expression for tumor-targeted gene therapy. Met, the receptor for hepatocyte growth factor (HGF), is overexpressed in many human cancers, and may contribute to their progression and metastasis. In this study, we constructed oncolytic adenovirus driven by hypoxia-inducible Met promoter (Ad/mickey), or by Met promoter (Ad/WHaT), and examined their cytolytic effects on mouse and human HCC cell lines. We found that ML-1 and Hep3B HCC cells expressed high levels of Met protein, whereas LL/2 and PC14PE6 lung cancer cells expressed low levels of Met protein. Moreover, the Met promoter activity was positively correlated with Met protein expression. Based on the difference in promoter activity, both viruses caused more severe cytolytic effects on ML-1 and Hep3B cells than on LL/2 and PC14PE6 cells. We also used CoCl2 to mimic hypoxic condition and found hypoxia-inducible Met promoter could be up-regulated under hypoxic condition compared with Met promoter. Meanwhile, Ad/mickey exhibited better oncolytic effects than Ad/WHaT, but its cytolytic effect was relatively attenuated under normoxia. We also found that rapamycin, an immunosuppressive drug, could enhance Met promoter activity and Ad/WHaT protein expression. The in vivo antitumor effects of Ad/mickey and Ad/WHaT were evaluated in terms of tumor growth and survival in BALB/c mice bearing syngeneic ML-1 tumors. Combination of Ad/WHaT and chemotherapy exhibited higher antitumor efficacy compared with either treatment alone. These results suggest that oncolytic adenovirus driven by the Met promoter had therapeutic potential for the treatment of HCC overexpressing Met.