在台灣，肝癌是目前最常發生的惡性腫瘤之一，其早期症狀不明顯且不易察覺，因此提供有效的治療是非常的重要。已有許多研究指出，具有複製能力的腺病毒能有效地毒殺腫瘤細胞，因此被視為嶄新的癌症治療法。腫瘤在生長的階段需要新生的血管提供氧氣及養分，並伴隨著腫瘤的惡化。因此，可藉由針對腫瘤局部缺氧的特性，增加對癌症的治療效果。目前有許多研究即利用 hypoxia response element (HRE)調控基因的表現，逹到對腫瘤細胞的專一毒殺作用。Met為肝細胞生長因子(hepatocytes growth factor, HGF)的受器，在許多人類癌症細胞中皆發現其過量表現，並扮演著促進腫瘤細胞生長及轉移的重要角色。在此研究中，我們利用腫瘤中Met過量表現，以及缺氧等特性，分別建構二隻由Met啟動子與受缺氧調控Met啟動子所趨動的腺病毒，分別命名為Ad/WHaT及Ad/mickey，並了解此病毒在小鼠與人類的肝細胞中所造成的毒殺作用。我們發現在小鼠ML-1及人類Hep3B肝癌細胞中，確實具有相當高的Met表現量，但在小鼠LL/2及人類PC14PE6肺癌細胞中，Met的表現量則低許多。基於Met啟動子的不同表現，二隻病毒皆能有效地對ML-1及Hep3B肝癌細胞造成較佳的毒殺作用。我們也利用CoCl2模擬缺氧的環境，並證明缺氧調控Met啟動子的確會受到缺氧的調控，而表現上升。同時，Ad/mickey在缺氧環境下的毒殺效果會較Ad/WHaT佳，但在有氧的情況下，二隻病毒所表現的差異則不大。我們也發現rapamycin，一種免疫抑制劑，能增加Met及Ad/WHaT的表現。在肝癌的動物實驗中，Ad/WHaT及Ad/mickey皆能有效地抑制腫瘤生長，並延長小鼠的壽命。Ad/WHaT結合rapamycin後，更能有效地提升其抗癌效果。由結果顯示，利用Met啟動子趨動一腺病毒能有效和安全地治療肝癌。

　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.

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