胰臟癌在美國為排名第四的癌症導致之死亡原因，且其病患的五年存活率在所有癌症病患中是最低的，只有9%。僅僅使用傳統的化療藥物來治療胰臟癌猶嫌不足，發展新的治療方式已是當務之急。溶瘤腺病毒為可以選擇性毒殺癌細胞而不會傷害正常細胞的病毒。將腺病毒改造為可以選擇性在癌細胞中複製最為常見的策略為將病毒的早期基因剔除，例如剔除E1A和E1B；另一種常見的策略為插入在癌細胞中活性特別強的啟動子來驅動病毒的早期基因表現。白血球介素-8 (interleukin-8，IL-8)在許多種癌症中都有表現量上升的趨勢，其中也包括胰臟癌。在先前本實驗室的研究中曾經構築了一個E1B55K基因缺失並以人類IL-8啟動子驅動的溶瘤腺病毒，命名為Ad.WSW。微小核醣核酸(microRNA，miR)是一群小型非編碼的RNA分子，且大部分的miR在癌症中都有表現量下降的情形，因為它們通常為腫瘤抑制基因，其中，miR-1在很多種癌症中的表現量都有下降，且具備良好的治療潛力。在本研究中，我們顯示了過度表現miR-1在胰臟癌細胞株中可以抑制細胞的增殖、細胞週期前進和促進細胞凋亡。因此，我們構築了一個以Ad.WSW為載體攜帶miR-1的重組溶瘤腺病毒，命名為Ad.WSW-miR-1，並用在胰臟癌的KPC小鼠模型中。結果顯示Ad.WSW-miR-1比起Ad.WSW能更有效地殺死人類和小鼠的胰臟癌細胞株，且對於正常的小鼠細胞株則不會有影響。對於KPC小鼠，Ad.WSW-miR-1也比起Ad.WSW更能抑制小鼠腫瘤的生長。因此，我們推論Ad.WSW-miR-1有潛力做為胰臟癌有效的治療藥物。

Pancreatic cancer is the fourth leading cause of death from cancer in the United States. The 5-year survival rate of pancreatic cancer is only 9%, which is the lowest for all cancers. The sole use of conventional chemotherapeutics is not enough to treat pancreatic cancer. Oncolytic adenovirus can selectively destroy cancerous cells and avoid damaging healthy tissues. The most common strategy to generate replication-selective adenovirus mutants is to delete the viral early genes, such as E1A and E1B. Another common strategy is to insert tumor-selective promoter to drive the expression of viral early genes. Interleukin-8 (IL-8) is often upregulated in many types of cancer, including pancreatic cancer. In our previous study, we generated an E1B55K-deleted oncolytic adenovirus driven by the human IL-8 promoter, designated Ad.WSW. MicroRNAs (miRs) are a group of small non-coding RNA molecules, most of which are downregulated in human cancers and function as tumor-suppressor genes. miR-1 is one of the most consistently downregulated miRs in human cancers and has a great therapeutic potential. In this study, we show that overexpression of miR-1 in pancreatic cancer cells can inhibit cell proliferation and cell cycle progression, as well as promote apoptosis. Therefore, we constructed a new recombinant adenovirus based on Ad.WSW carrying miR-1, designated Ad.WSW-miR-1, and tested its oncolytic activity for the treatment of pancreatic cancer in the KPC mouse model. Our results show that Ad.WSW-miR-1 much efficiently killed human and murine pancreatic cancer cells than Ad.WSW. Moreover, it was not cytolytic to normal murine cells. Ad.WSW-miR-1 also much efficiently inhibited tumor growth in KPC mice than Ad.WSW. We conclude that Ad.WSW-miR-1 has the potential to be an effective strategy for the treatment of pancreatic cancer.

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