肺癌為高致死以及高好發率疾病。在所有肺癌病例當中，約80%為
非小細胞肺癌，其餘則為小細胞肺癌。與正常細胞相同，肺癌細胞也會表現受體酪氨酸激 (receptor tyrosine kinase，RTK)，不同的是，肺癌細胞上的RTK 常因為大量表現或突變而過度活化，使得癌細胞生長不受正常調控。c-Met 是一種RTK，當不正常受到肝細胞生長因子刺激或本身過度活化使得細胞產生變異或腫瘤特性。c-Met 也參與許多種癌細胞包括肺癌細胞的生長、侵略以及轉移。我們使用由c-Met 啟動子調控複製的E1B55KD 基因剔除溶瘤腺病毒治療肺癌。結果顯示，Ad.What可選擇性地在c-Met 啟動子活性較強的肺癌細胞中複製，進而毒殺肺癌細胞，對於正常細胞則無太大影響。過去研究顯示，合併化療藥物及溶瘤腺病毒能增強毒殺腫瘤的效果。rapamycin 為rapamycin 的哺乳動物目標物 (Mammalian Target of Rapamycin，mTOR) 絲氨酸/羥丁胺酸激高度專一抑制物，已經在許多癌症治療上得到一定的效果。因此我們合併rapamycin 與Ad.What 共同作用，並進一步發現rapamycin 與Ad.What在毒殺肺癌細胞上能達到所謂的“協同作用”。接著我們發現rapamycin增加肺癌細胞上克沙奇病毒及腺病毒受體以及αV 細胞表面黏著分子表現。另一方面，Ad.What 降低肺癌細胞中mTOR 下游因子p70S6K 以及誘發細胞產生細胞自噬作用。由以上結果顯示，以c-Met 啟動子驅動的溶瘤腺病毒合併rapamycin 有潛力作為有效且安全的肺癌治療選擇。

Lung cancer is a deadly disease with high mortality and morbidity. Approximately 85% of these cases are non-small cell lung cancer (NSCLC) with the rest being small cell lung cancer (SCLC). Like normal cells, lung cancer cells express receptor tyrosine kinases. The difference is that these receptors may be overexpressed or mutated leading to increased activation. c-Met is a receptor tyrosine kinase whose activation by hepatocyte growth factor can lead to transformation and tumorigenicity. It is also implicated in growth, invasion, and metastasis of various tumors, including lung cancer. Here, we used an E1B 55KD-deleted replication-selective oncolytic adenovirus (Ad.What) driven by the c-Met promoter for the treatment of
lung cancer. Ad.What replicated and hence lysed lung cancer cells with c-Met overexpression, whereas it did not induce noticeable cytopathic effects in normal cells. Previous studies showed that combination of oncolytic adenovirus with chemotherapeutic drugs could augment the
antitumor efficacy. Rapamycin, a highly selective inhibitor of mammalian target of rapamycin (mTOR) serine/threonine kinase, has shown promise in
clinical studies for treating different types of cancer. Accordingly, we combined rapamycin with Ad.What and found that they synergized in inducing cytopathic effects in lung cancer cells. Rapamycin enhanced coxsackievirus and adenovirus receptor (CAR) and αV integrin expression
on cancer cells. Ad.What reduced total p70S6K and phosphorylated p70S6K, the downstream effector of mTOR, and induced autophagy. We concluded that the combination of c-Met promoter-driven oncolytic adenovirus with rapamycin has the potential to be an effective strategy for lung cancer treatment.

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